MX2012011045A - Chemical compounds. - Google Patents

Abstract

The invention is directed to substituted indoline derivatives. Specifically, the invention is directed to compounds according to Formula I wherein R1, R2 and R3 are defined herein. The compounds of the invention are inhibitors of PERK and can be useful in the treatment of cancer, ocular diseases, and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes Parkinson disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, and arrhythmias, and more specifically cancers of the breast, colon, pancreatic, and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting PERK activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

NOVEDOSOS DERIVADOS DE INDOLINA SUBSTITUIDOS FIELD OF THE INVENTION The present invention relates to substituted indoline derivatives which are inhibitors of the activity of ER kinase type protein kinase R (PKR), PERK. The present invention also relates to pharmaceutical compositions comprising said compounds and methods of using said compounds in the treatment of cancer, eye diseases and diseases associated with activated deployed protein response pathways, such as Alzheimer's disease, stroke, Type 1 diabetes, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis and arrhythmias.

BACKGROUND OF THE INVENTION The unfolded protein response (UPR) is a signal transduction pathway that allows cells to survive environmental stresses that disrupt the folding and maturation of proteins in the endoplasmic reticulum (ER) (Ma and Hendershot, 2004), (Feldman et al., 2005), (Koumenis and Wouters, 2006). Stress stimuli that activate UPR include hypoxia, impaired protein glycosylation (glucose deprivation), decreased calcium in the luminal ER, or changes in the redox state of the ER (Ma and Hendershot, 2004), (Feldman et al. al., 2005). These perturbations result in the accumulation of unfolded or misfolded proteins in the ER, which is detected by resident ER membrane proteins. These proteins activate a coordinated cellular response to alleviate the impact of stress and enhance cell survival. The responses include an increase in the level of chaperone proteins to enhance protein refolding, degradation of misfolded proteins, and arrest of translation to decrease the load of proteins entering the ER. These routes also regulate cell survival by modulating apoptosis (Ma and Hendershot, 2004), (Feldman et al., 2005), (Hamanaka et al., 2009) and autophagy (Rouschop et al.), And can trigger death Cell in conditions of prolonged stress of the ER.

Three ER membrane proteins have been identified as primary effectors of the UPR: RE kinase of protein kinase type R (PKR) [PERK, also known as kinase 3 of eukaryotic initiation factor 2A (EIF2AK3), or pancreatic kinase elF2a ( PEK)], a gene that requires inositol 1 a / ß (IRE1), and activating transcription factor 6 (ATF6) (Ma and Hendershot, 2004). Under normal conditions, these proteins are maintained in the inactivated state by binding to the ER chaperone, GRP78 (BiP). The accumulation of proteins deployed in the ER leads to the release of GRP78 from these sensors, resulting in their activation (Ma et al., 2002). PERK is a type I ER membrane protein that contains a stress sensitive domain against the ER lumen, a transmembrane segment and a cytosolic kinase domain (Shi et al., 1998), (Sood et al., 2000 ). The release of GRP78 from the stress-sensitive domain of PERK results in oligomerization and autophosphorylation in multiple residues of serine, threonine and tyrosine (Ma et al., 2001), (Su et al., 2008). The main substrate for PERK is the eukaryotic initiation factor 2a (elF2a) in serine-51 (Marciniak et al., 2006). This site is also phosphorylated by other members of the PERK family [(general control not derepressed 2 (GCN2), PKR, and heme regulated kinase (HRI)] in response to different stimuli, and by pharmacological inducers of ER stress such as tapsigargine and tunicamycin The phosphorylation of elF2a makes it an inhibitor of elF2B, which prevents the binding of the initiation complex of the translation of the ribosome 40S and therefore reduces the speed of translation initiation. to a loss of cyclin D1 in cells, resulting in the arrest in the G1 phase of the cell division cycle (Brewer and DiehI, 2000), (Hamanaka et al., 2005) Paradoxically, the translation of certain messages encoding effectors downstream of elF2a, ATF4 and CHOP (homologous protein of C / EBP; GADD 53), which modulate cell survival routes, actually increases due to ER stress. A second substrate of the PERK, Nrf2, regulates cellular redox potential, contributes to cell adaptation to ER stress and promotes survival (Cullinan and DiehI, 2004). The normal function of PERK is to protect the secretory cells ER stress protectors. The phenotypes of mice that do not express PERK include diabetes, due to the loss of pancreatic islet cells, skeletal abnormalities and growth retardation (Harding et al., 2001), (Zhang et al., 2006), ( lida et al., 2007). These characteristics are similar to those seen in patients with Wolcott-Rallison syndrome, who carry germline mutations in the PERK gene (Delepine et al., 2000). IRE1 is a transmembrane protein with kinase and endonulease functions (RNAse) (Feldman et al., 2005) (Koumenis and Wouters, 2006). Under ER stress, it undergoes oligomerization and autophosphorylation, which activates the endonuclease to remove an intron from the mRNA of the non-spliced X-box binding protein (XBP1). This leads to the synthesis of truncated XBP1, which activates the transcription of the UPR genes. The third UPR effector, ATF6, is transported to the golgi apparatus after ER stress, where it is cleaved by proteases to release the cytosolic transcription domain. This domain translocates to the nucleus and activates the transcription of UPR genes (Feldman et al., 2005), (Koumenis and Wouters, 2006).

Tumor cells undergo episodes of hypoxia and nutrient deprivation during their growth due to inadequate blood supply and aberrant blood vessel function (Brown and Wilson, 2004), (Blais and Bell, 2006). Therefore, it is likely that they are dependent on the active UPR signaling to facilitate their growth. Consistent with this, mouse fibroblasts derived from PERK - / -, XBP1 - / - and ATF4 - / - mice, and fibroblasts expressing mutant elF2a exhibit lower clonogenic growth and increased apoptosis under hypoxic conditions in vitro and grow at substantially reduced when implanted as tumors in mice without an immune system (Koumenis et al., 2002), (Romero-Ramírez et al., 2004), (Bi et al., 2005). Human tumor cell lines carrying a dominant negative PERK lacking kinase activity also showed increased in vitro apoptosis with hypoxia and impaired tumor growth in vivo (Bi et al., 2005). In these studies, the activation of the UPR was observed in regions in the tumor that coincided with hypoxic zones. These areas showed higher rates of apoptosis compared to tumors with intact UPR signaling. An additional test that supports the role of PERK in the promotion of tumor growth, is the observation that the number, size and vascularity of insulinomas that appear in transgenic mice expressing the SV40 T antigen in insulin secreting beta cells, it had been greatly reduced in PERK - / - mice compared to the genetically intact control (Gupta et al., 2009). Activation of the UPR has also been observed in clinical samples. Human tumors, including those derived from cervical carcinomas, glioblastomas (Bi et al., 2005), lung cancers (Jorgensen et al., 2008) and breast cancers (Amerí et al., 2004), (Davies et al., 2008) show high levels of proteins involved in UPR, compared with normal tissues. Therefore, it is expected that the inhibition of the response to proteins deployed with compounds that block the activity of PERK and other components of the UPR, have utility as anticancer agents in the treatment of diseases associated with the routes of responses to activated activated proteins, such as Alzheimer's disease, stroke and type 1 diabetes.

The loss of homeostasis of the endoplasmic reticulum and the accumulation of misfolded proteins can contribute to a series of pathological conditions including cardiovascular and degenerative diseases (Paschen, 2004) such as: Alzheimer's disease '(Salminen et al., 2009 and O' Connor et al., 2008), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (Kanekura et al., 2009 and Nassif et al., 2010), myocardial infarction, cardiovascular disease, atherosclerosis (McAlpine et al., 2010) , and arrhythmias. It is expected that a PERK inhibitor is useful in the treatment of such cardiovascular and degenerative diseases, in which the underlying pathology and symptoms are associated with deregulation of the response to unfolding proteins.

Bibliography Ameri, K., Lewis, C.E., Raida, M., Sowter, H., Hai, T., and Harris, A.L. (2004). "Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells", Blood 103, 1876-82.

Bi, M., Naczki, C, Koritzinsky, M., Fels, D., Blais, J., Hu, N., Harding, H., Novoa, I., Varia, M., Raleigh, J., et. to the. (2005). "ER stress-regulation translation increases tolerance to extreme hypoxia and promotes tumor growth", EMBO J. 24, 3470-81.

Blais, J., and Bell, J. C. (2006). "Novel therapeutic target: the PERKs of inhibiting the integrated stress response", Cell Cycle 5, 2874-7.

Brewer, J. W., and Diehl, J. A. (2000). "PERK mediates cell-cycle exit during the mammalian unfolded protein response", Proc. Nati Acad. Sci. USA 97, 12625-30.

Brown, J. M., and Wilson, W. R. (2004). "Exploiting tumor hypoxia in cancer treatment", Nat. Rev. Cancer 4, 437-47.

Cullinan, S. B., and Diehl, J. A. (2004). "PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress", J. Biol. Chem. 279, 20108-17.

Davies, M.P., Barraclough, D.L. Stewart, C, Joyce, K.A., Eccles, R.M., Barraclough, R., Rudland, P.S., and Sibson, D.R. (2008). "Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer", Int. J. Cancer 123, 85-8.

Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., and Julier, C. (2000). "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome", Nat. Genet. 25, 406-9.

Feldman, D. E., Chauhan, V., and Koong, A. C. (2005). "The unfolded protein response: a novel component of the hypoxic stress response in tumors", Mol. Cancer Res. 3, 597-605.

Gupta, S., McGrath, B "and Cavener, D. R. (2009). "PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice", PLoS One 4, e8008.

Hamanaka, R.B., Bennett, B.S., Cullinan, S.B., and Diehl, J.A. (2005). "PERK and GCN2 contribute to elF2alpha phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway", Mol. Biol. Cell 16, 5493-501.

Hamanaka, R.B., Bobrovnikova-Marjon, E., Ji, X., üebhaber, S.A., and Diehl, J.A. (2009). "PERK-dependent regulation of IAP translation during ER stress", Oncogene 28, 910-20.

Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., and Ron, D. (2001). "Diabetes mellitus and exocrine pancreatic dysfunction in perk - / - mice reveal a role for translational control in secretory cell survival", Mol. Cell 7, 1153-63. lida, K., Li, Y., cGrath, B. C, Frank, A., and Cavener, D. R. (2007). "PERK elF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice", BMC Cell Biol. 8, 38.

Jorgensen, E., Stinson, A., Shan, L, Yang, J., Gietl, D., and Albino, A. P. (2008). "Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells", BMC Cancer 8, 229.

Kanekura, K .; Suzuki, H .; Aiso, S .; Matsuoka, M. "ER Stress and Unfolded Protein Response Amyotrophic Lateral Sclerosis", Molecular Neurobiology (2009), 39 (2), 81-89.

Koumenis, C, Naczki, C, Koritzinsky, M., Rastani, S., Diehl, A., Sonenberg, N., Koromilas, A., and Wouters, B. G. (2002). "Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor elF2alpha", Mol. Cell Biol. 22, 7405-16.

Koumenis, C, and Wouters, B. G. (2006). "Translating" hypoxia tumor: unfolded protein response (UPR) -dependent and UPR-independent pathways, Mol. Cancer Res. 4, 423-36.

Ma, K., Vattem, K. M., and Wek, R. C. (2002). "Dimerization and relapse of molecular chaperone inhibition facilitates activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress", J. Biol. Chem. 277, 18728-35.

Ma, Y., and Hendershot, L. M. (2004). "The role of the unfolded protein response in tumor development: friend or foe?", Nal Rev. Cancer A, 966-77.

Ma, Y., Lu, Y., Zeng, H., Ron, D., Mo, W., and Neubert, T. A. (2001). "Characterization of phosphopeptides from protein digests using matrix-assisted laser desorption / ionization time-of-flight mass spectrometry and nanoelectrospray quadrupole time-of-flight mass spectrometry", Rapid Commun Mass Spectrom 15, 1693-700.

Marciniak, S.J., García-Bonilla, L, Hu, J., Harding, H.P., and Ron, D. (2006). "Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK ", J. Cell Biol. 172, 201-9.

McAlpine, C.S .; Bowes, A.J .; and Werstuck, G.H. (2010) "Diabetes, hyperglycemia and accelerated atherosclerosis: evidence supporting a role for endoplasmic reticulum (ER) stress signaling". Cardiovascular & Hematological Disorders: Drug Targets 10 (2), 151-157.

Nassif, M. Matus, S .; Castillo, K .; and Hetz, C. (2010) "Amyotrophic Lateral Sclerosis Pathogenesis: A Journey Through the Secretory Pathway" Antioxidants & Redox Signaling 13 (12), 1955-1989.

O'Connor, T .; Sadleir, K.R .; aus, E .; Velliquette, R. A .; Zhao, J .; Cole, S. L; Eimer, W. A .; Hitt, B .; Bembinster, L A .; Lammich, S. Lichtenthaler, S.F., Hébert, S.S., De Strooper, B., Haass, C, Bennett, D.A., Vassar, R. (2008) "Phosphorylation of the translation initiation factor elF2a increases BACE1 levéis and promotes amyloidogenesis". Neuron, 60 (6), 988-1009.

Paschen, W. (2004) "Endoplasmic reticulum dysfunction in brain pathology: Critical role of protein synthesis", Current Neurovascular Research, 1 (2), 173-181.

Romero-Ramírez, L., Cao, H., Nelson, D., Hammond, E., Lee, AH, Yoshida, H., Mori, K., Glimcher, LH, Denko, N.C., Giaccia, AJ, et al. (2004). "XBP1 is essential for survival under hypoxic conditions and is required for tumor growth", Cancer Res 64, 5943-7.

Rouschop, K.M., van den Beucken, T., Dubois, L., Niessen, H., Bussink, J., Savelkouls, K., Keulers, T., Mujcic, H., Landuyt, W., Voncken, J.

W., et al. "The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy MAP1 LC3B and ATG5 genes", J. Clin. Invest. 120, 127-41.

Salminen, A .; Kauppinen, A .; Suuronen, T .; Kaarniranta, K .; Ojala, J. "ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology". Journal of Neuroinflammation (2009), 6:41.

Shi, Y., Vattem, K.M., Sood, R., An, J., Liang, J., Stramm, L, and Wek, R. C. (1998). "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control", Mol. Cell. Biol 18, 7499-509.

Sood, R., Porter, A.C., Ma, K., Quilliam, L.A., and Wek, R.C. (2000). "Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress", Biochem. J. 346 Pt 2, 281 -93.

Su, Q., Wang, S., Gao, H. Q., Kazemi, S., Harding, H. P., Ron, D., and Koromilas, A. E. (2008). "Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation", J. Biol. Chem. 283, 469-75.

Tabas, I .; Seimon, T .; Timmins, J .; Li, G .; Lim, W. "Macrophage apoptosis in advanced atherosclerosis", Annals of the New York Academy of Sciences (2009), 1 173 (S1), E40-E45.

Zhang, W., Feng, D., Li, Y., Lida, K., McGrath, B., and Cavener, D. R. (2006). "PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis", Cell Metab. 4, 491-7.

An object of the present invention is to provide new compounds that are inhibitors of PERK.

It is also an object of the present invention to provide pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention.

It is also an object of the present invention to provide a method of treating cancer and diseases associated with the response pathways to activated deployed proteins, such as Alzheimer's disease, stroke, type 1 diabetes, Parkinson's disease, Huntington's disease. , amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis and arrhythmias, which comprises administering said inhibitors of PERK activity.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the invention is directed to substituted indoline derivatives, specifically to compounds according to formula I: wherein R1, R2 and R3 are defined below.

The present invention also relates to the discovery that the compounds of formula (I) are active as inhibitors of PERK.

This invention also relates to a method for treating cancer, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) that inhibits PERK.

This invention also relates to a method for treating Alzheimer's disease, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) that inhibits PERK.

This invention also relates to a method for treating stroke, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) that inhibits PERK.

This invention also relates to a method for treating type 1 diabetes, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) that inhibits PERK.

This invention also relates to a method for treating a pathological condition selected from: Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis and arrhythmias, which comprises administering to a subject in need thereof an amount effective of a compound of formula (I) that inhibits PERK.

In a further aspect of the invention new methods and new intermediates useful in the preparation of the PERK inhibitor compounds of the present invention are provided.

Pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention are included in the present invention.

Coadministration methods of the PERK inhibitor compounds of the present invention with other active ingredients are also included in the present invention.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to new compounds of formula (I): in which: R1 is selected from: bicycloheteroaryl, and bicycloheteroaryl substituted with 1 to 5 substituents, independently selected from: halogen, C .Q alkyl, Alkyloxy Cu, -OH, hydroxyalkyl C1.4, -COOH, -CONH2, tetrazol, -CF3, -alkyl (Ci-4) -0-alkyl (Ci-4), -CH2CH2N (H) C (O) OCH2aryl, di (Ci-4 alkyl) -aminoalkyl (Ci.4), aminoalkyl (Ci-4), -NO2, -NH2, -CN, aril, aryl substituted with 1 to 3 substituents independently selected from: Ci_4 alkyl, di- (Ci-4 alkyl) -amino- (C1.4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heterocycloalkyl, Heterocycloalkyl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl, di- (Ci.4 alkyl) -amino- (C1-4 alkyl), fluoro, chloro, bromo, iodo and -CF3, (alkyl Ci-4) -heterocycloalkyl, (Ci-alkyl) -heterocycloalkyl substituted with 1 to 3 substituents independently selected from: C1.4 alkyl, di- (Ci-4 alkyl) -amino- (C-M alkyl), fluoro, chloro, bromo, iodo and-CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: Ci-4alkyl, di- (Ci-ι-amino-alkyl- (C-4-alkyl), fluoro, chloro, bromo, iodo and -CF3; R2 is selected from: aril, aryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C -4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CONH2, -CF3, - (C1-4 alkyl) -0 - (C1-4 alkyl), -N02, -NH2 and -CN, heteroaryl, heteroaryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C ^ alkyl, alkyloxy d.4, -OH, -COOH, -CONH2, -CF3, - (alkyl C ^ Halkyls Ci-4) , -NO2, -NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4 alkyl, C -4 alkyloxy, -OH, -COOH, -CONH2, -CF3, - (C1-4 alkyl) -O- (Ci-4 alkyl) , -NO2 > -NH2 and -CN; Y R3 is selected from: hydrogen, fluoro, chloro, bromo and iodo; and you come out of them.

This invention also relates to pharmaceutically acceptable salts of the compounds of formula (I).

Suitably the compound of formula (I) is not 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (3-pyridinyl) thieno [3,2-c] ] pyridin-4-amine.

For the compounds of formula (I), suitably R1 is bicycloheteroaryl substituted with 1 to 3 substituents independently selected from: halogen, C-i-6 alkyl, Alkyloxy d-4, -OH, Hydroxyalkyl Ci-, -COOH, -CONH2, tetrazol, -CF3, -alkyl (Ci-) -O-alkyl (Ci.4), -CH2CH2N (H) C (O) OCH2aryl, di (Ci-4 alkyl) -aminoalkyl (Ci.4), aminoalkyl (Ci-4), -NO2, -NH2, -CN, aril, aryl substituted with 1 to 3 substituents independently selected from: C1.4 alkyl, di- (C1-4 alkyl) -amino- (C1.4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heterocycloalkyl, heterocycloalkyl substituted with 1 to 3 substituents independently selected from: C-alkyl, di- (Ci-4 alkyl) -amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3, (alkyl Ci-4) -heterocycloalkyl, (alkyl Ci-4) -heterocycloalkyl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl di- (Ci-4 alkyl) -amino- (Ci-) alkyl, fluoro, chloro, bromo, iodo and-CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: C 1-4 alkyl, di- (C 1-4 alkyl) -amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3, For the compounds of formula (I), suitably R1 is bicycloheteroaryl substituted with 1 to 3 substituents independently selected from: halogen, Ci.6 alkyl, Ci.4 alkyloxy, -OH, hydroxyalkyl Ci-4 > -COOH, tetrazol, -CF3, -alki Ci ^ -O-AlkyiCi ..)), -CH2CH2N (H) C (0) OCH2aryl, d (alkyl C-i-4) -aminoalkyl (Ci-4), aminoalkyl (Ci-4), -N02, -NH2, -CN, aril, aryl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl, di- (alkyl Ci-) -amino- (Ci-4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heterocycloalkyl, Heterocycloalkyl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl, di- (C1-) alkyl- amino- (Ci, 4 alkyl), fluoro, chloro, bromo, iodo and -CF3i (alkyl Ci-4) -heterocycloalkyl, (C 4 alkylheterocycloalkyl substituted with 1 to 3 substituents independently selected from: C 4 alkyl, di- (alkyl Ci-) -amino- (Ci_ alkyl), fluoro, chloro, bromo, iodo and - CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: C 1-4 alkyl, di- (C 1-4 alkyl- amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3, For the compounds of formula (I), suitably R1 is selected from the following bicycloheteroaryls, in which the joint position is designated by a wavy line: Y R2 is selected from: aryl, aryl substituted with 1 to 3 substituents independently selected from: halogen, alkyl d-4, alkyloxy C- | 4, -OH, -COOH, -CF 3, - (C 4 alkyl) -O- (C 4 alkyl) , -NO2) -NH2 and -CN, heteroaryl, heteroaryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4-alkyl, Ci-4-alkyloxy, -OH, -COOH, -CF3, - (Ci-4-alkyl) -O- (alkyl) C -), -NO2, -NH2 and -CN; Y R3 is selected from: hydrogen, fluoro and chloro.

Suitably, this invention relates to new compounds of formula (IA): in which: R1 is selected from: bicycloheteroaryl, and bicycloheteroaryl substituted with 1 to 5 substituents selected from: halogen, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, tetrazol, -CF3, -alkyl (Ci-4) -O-alkyl (Ci-4), -NO2, -NH2, -CN, aril, aryl substituted with 1 to 3 substituents selected from: alkyl C-i-4, di- (C1-4 alkyl) -amino- (C1.4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heterocycloalkyl, heterocycloalkyl substituted with 1 to 3 substituents selected from: Ci-4 alkyl, di- (Ci-4 alkyl) -amino- (Ci-) alkyl, fluoro, chloro, bromo, iodo and -CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents selected from: C -4 alkyl, di- (Ci-4 alkyl) -amino- (Ci-4 alkyl), fluoro, chloro, bromo, iodo and -CF3; Y R2 is selected from: aril, aryl substituted with 1 to 5 substituents selected from: fluoro, chloro, bromo, iodo, C- alkyl, C-, -OH, -COOH, -COOH, -CF3, - (Ci-4 alkyl) -0- (alkyloxy) -4), -N02, -NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents selected from: fluoro, chloro, bromo, iodo, Ci-4 alkyl, Ci-, oxy, -COOH, -CF3, - (Ci-4 alkyl) -0- (Ci- ), -N02l -NH2 and -CN; and you come out of them.

This invention also relates to pharmaceutically acceptable salts of the compounds of formula (IA).

Suitably, the compound of formula (IA) is not 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (3-pyridinyl) thieno [3,2-c] ] pyridin-4-amine.

For compounds of formula (IA), suitably R1 is bicycloheteroaryl substituted with 1 to 3 substituents selected from: halogen, Ci-4 alkyl, C -4 alkyloxy, -OH, -COOH, tetrazol, -CF3, -alkyl (Ci-4) -0-alkyl (Ci-4), -N02, -NH2, -CN, aril, aryl substituted with 1 to 3 substituents selected from: C-i-4 alkyl, di- (Ci-4 alkyl) -amino- (Ci-4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heterocycloalkyl, heterocycloalkyl substituted with 1 to 3 substituents selected from: Ci-4 alkyl, di- (Ci-4 alkyl) -amino- (Ci-4 alkyl), fluoro, chloro, bromo, iodo and -CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents selected from: Ci-4 alkyl, di- (C-M alkyl) -amino- (C-4 alkyl), fluoro, chloro, bromo, iodo and -CF3.

For compounds of formula (IA), suitably R1 is selected from: Y R2 is selected from: aril, aryl substituted with 1 to 3 substituents selected from: halogen, C 1-4 alkyl, alkyloxy d-4, -OH, -COOH, -CF 3, - (alkyl CM) -0- (C 1-4 alkyl), -N02, - NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 3 substituents selected from: halogen, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF 3, - (Ci-4 alkyl) -O- (C 1-4 alkyl), -NO 2 , -NH2 and -CN.

Suitably, this invention relates to new compounds of formula (IB): in which: R1 is selected from: bicycloheteroaryl, and bicycloheteroaryl substituted with 1 to 5 substituyent selected from: halogen, Ci-, alkyl, Ci ^, -OH, -COOH, -CF3 (alkyl Ci-) -O- (Ci-4 alkyl), aryl, heteroaryl, -NO2, -NH2 and -CN, and R2 is selected from: aril, aryl substituted with 1 to 5 substituents selected from: halogen, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF3, - (Ci.4 alkyl) -O- (Ci-4 alkyl), -NO2 , -NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents selected from: halogen, C1- alkyl, alkyloxy Cu, -OH, -COOH, -CF3, - (alkyl Ci-4) -O- (alkyl d-4), -NO2, -NH2 and -CN; and you come out of them.

This invention also relates to pharmaceutically acceptable salts of the compounds of formula (IB).

Suitably the compound of formula (IB) is not 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (3-pyridinyl) thieno [3,2-c] ] pyridin-4-amine.

For the compounds of formula (1 B), suitably R 1 is bicycloheteroaryl substituted with 1 to 3 substituents selected from: halogen, C 1 - alkyl, C 1 alkyloxy, -OH, -COOH, -CF 3, - (Ci-4 alkyl) - O- (Ci-4 alkyl), aryl, heteroaryl, -NO2, -NH2 and -CN.

For compounds of formula (1 B), suitably R1 is selected from: R2 is selected from: aril, aryl substituted with 1 to 3 substituents selected from: halogen, C1-4 alkyl, C1-4 alkyloxy, -OH, -COOH, -CF3, - (C1-4 alkyl) -O- (C1.4 alkyl), -NO2 , -NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 3 substituents selected from: halogen, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF 3, - (Ci-4 alkyl) -O- (C 1-4 alkyl), -NO 2 , -NH2 and -CN.

They are included in the compounds of formula (I) of the present invention: 1 - . 1 - . 1-methyl-3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -1 H -pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-H-indol-5-yl} -1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1H-indol-5-yl] -1 H -pyrazolo [3,4-d] pyrimidin-4-amine 7-methyl-5- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7H-pyrrolo [2,3- d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (3-pyridinyl) thieno [3,2-c] pyridin-4-amine; 1 -methyl-4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H -indazol-3-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (4-pyridinyl) thieno [3,2-c] pindin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-pindinyl) thieno [3,2-c] pindin-4-amine; 3- . { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-3-yl) thieno [3,2-c] pyridin-4-amine; 4- . { 1 - [(2,5-difluorophenyl) acetyl] -2,3-di idro-1 H-indol-5-yl} -1-methyl-1 H -indazol-3-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (1 H -pyrazol-4-yl) thieno [3,2-c] pyridin-4-amine; 7- (1-methyl-1 H -pyrazol-4-yl) -3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridine -4-amine; 3-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluorophenyl) acetyl] -2, 3-d ihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1 - (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (1, 2,3,6-tetrahydro-4-pyridinyl) thieno [3,2-c] pyridin-4-amine; 3- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3- (1- { [3- (methyloxy) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- [1- (2-naphthalenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (4-piperidinyl) thieno [3,2-c] pyridin-4-amine; 7- { 3 - [(dimethylamino) methyl] phenyl} -3- [1- (phenylacetyl) -2,3-dihydro-1H- indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [2,3-d] pyrimidin-4-annin; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-cJpyridin-4-amine; 7-methyl-5-. { 1 - [(3-methylphenyl) acetyl) -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3-. { 2- [5- (4-aminothieno [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indol-1-yl] -2-oxoethyl} benzonitrile; 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-Dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-H-pyrazolo [3,4-d] pyrimidine- 4-amine; 7-methyl-5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] ] pyrimidin-4-amine; 5-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine; 1-methyl-3- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4- d] pyrimidin-4-amine; 7-methyl-5- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3 -d] pyrimidine-4-amine 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrrazolo [3,4-d] pyrimidn-4-amino; 1-methyl-3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4- d] pyridin-4-amine; 5-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-D-fluoro-phenyl) -acetyl] -2,3-dihydro-1 H -indole-5-yl} furo [3,2-c] pyridin-4-amino; 1-methyl-3-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrrazolo [3,4-d] pyrimidin-4-amino; 5-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimid-4-amino; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-4-yl) furo [3,2-c] pyridin-4-amino; 3-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrrazolo [3,4-d] pyrimid-4-amino; 5-. { 1 - [(2,5-difluorophenol) acetl] -2,3-dihydro-1 H -indole-5-yl} -7-methy1-7H-pyrrolo [2,3-d] pyrimidin-4-amino; 3-. { 1 - [(2,5-difluorophenol) acetyl] -2,3-d, 1-hydro-1-indol-5-yl} -7- (1 H-pyrazol-4-yl) t-ene [3,2-c] pyridn-4-amino; 3-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methyl-4-pipendinyl) -7H-pyrrolo [2,3-d] pinmidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 1-methyl-3-. { 1 - [(1-methyl-1 H-pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 5-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pinmidin-4-amine; 5-. { 1 - [(2-fluoro-3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2-fluoro-3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methyl-4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-chloro-4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,3-Dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 1 - . 1- (1-methyl ethyl) -3-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 2- (4-amino-3- { 1 - [(3-methylene] acetyl] -2,3-dihydro-1 H-indol-5-yl}. -1 H-pyrazolo [3,4-d] pyrimidin-1-yl) ethanol; 5-. { 1 - [(3,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-p -peridinyl) -7H-pyrrolo [2,3-d] pyrimidn-4-amin! 1-ethyl-3-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -1 H-pyrrazolo [3,4-d] pyrimidn-4-amino; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methylfuro [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1- (1-methylethyl) -1 H -pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- (3-azetidinyl) -5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(4-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-2,4-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5- (1- { [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 7 - [(methoxy) meth] -5-. { 1 - [(3-methylphenyl) acetyl] -2,3-d, 1-d-1-H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(1-methyl-1 H-pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(5-chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,4-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3,4-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; [2- (4-amino-3- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl.} Furo [3,2-c] Phenylmethyl pyridyl-7-yl) ethyl] carbamate; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- (dimethylamino) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(6-chloro-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-chloro-2,4-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-meth1l-1 H-pyrazolo [3,4-d] pyrimidine-4-amine 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amino; 4-amino-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridine-7-carbonitrile; 5-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5- [4-fluoro-1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 4-Fluoro-1 - [(1-methyl-1 H -pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [2,3-d] pyrimidin-4-amine; 5- (1 - { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [2,3-d] pyrimidin-4-amine; 5- (1 - { [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) furo [2,3-d] pyrimidine -4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- (4-piperidinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(6-methyl-2-pyridyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5- (1 - { [4-fluoro-3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-di idro-1 H-indol-5-yl} -7- [2- (dimethylamino) ethyl] furo [3,2-c] pyridin-4-amine; 7-methyl-5- (1- { [6- (tnfluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2, 3-d] pyrimidin-4-amine; 7- (3-oxetanyl) -5- (1- {[[3- (tnfluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 7- [2- (4-morpholinyl) ethyl] -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) - 7H-pyrrolo [2,3-d] pinmidin-4-amine; 7- (1-methylethyl) -5- (1 - { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- (3-methylbutyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-c] pyridin-3-amine; 7-chloro-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 7- (3-azetidinyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2 , 3-d] pinmidin-4-amine; 7- (1-methyl-3-azetidinyl) -5- (1 - { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H -pyrrolo [2,3-d] pyrimidin-4-amine; 7- [2- (dimethylamino) ethyl] -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H- pyrrolo [2,3-d] pyrimidin-4-amine; 5- (4-Fluoro-1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 5-. { 4-Fluoro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5- (4-Fluoro-1- {[[6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H- pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -4-fluoro-2,3-dihydro-1 H -indole-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidn-4-amine; 5- (4-fluoro-1- {[4-fluoro-3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H -pyrrolo [2,3-d] pyrimidin-4-amine; 3- . { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 5-. { 4-fluoro-1 - [(4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-annin; 4- (1 - { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4-c] pyridin- 3-amine; 1-methyl-4- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4- c] pyridin-3-amine; 7- (3-azetidinyl) -5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- [2- (4-piperidinyl) ethyl] -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) - 7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5- (1 - { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H -pyrrolo [2,3-d] pyrimidine- 4-amine; 5-. { 4-Chloro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; Y 5- (4-chloro-1- {[[6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H- pyrrolo [2,3-d] pyrimidin-4-amine; and salts thereof including their pharmaceutically acceptable salts.

The person skilled in the art will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to formula I can be prepared. Indeed, in some embodiments of the invention, salts including pharmaceutically salts may be preferred. acceptable of the compounds according to formula I, against the respective free bases. Accordingly, the invention further relates to salts, including pharmaceutically acceptable salts of the compounds according to formula I.

The salts of the compounds of the invention are readily prepared by those skilled in the art.

The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those skilled in the art.

The compounds according to formula I may contain one or more asymmetric centers (also referred to as chiral centers) and, therefore, may exist as individual enantiomers, diastereoisomers or other stereoisomeric forms, or in the form of mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent, such as in an alkyl group. When the stereochemistry of a chiral center present in a compound of formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to include all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

The compounds according to formula I may also contain double bonds or other centers of geometric asymmetry. When I do not know specifying the stereochemistry of a center of geometric asymmetry present in formula I, or in any chemical structure illustrated herein, is intended to encompass the geometric isomer trans (E), the geometric isomer cis (Z), and all the mixtures thereof. Similarly, in formula I all tautomeric forms are also included, such tautomers exist in equilibrium or are predominantly in one form.

The compounds of formula I or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention can exist in crystalline form or in non-crystalline form or as a mixture of both. For the compounds of the invention that are in crystalline form, the person skilled in the art will appreciate that pharmaceutically acceptable solvates can be formed in which solvent molecules are incorporated within the crystal lattice, during crystallization. Solvates in which water is the solvent that is incorporated into the crystal lattice are typically referred to as "hydrates". Hydrates include stoichiometric hydrates and also compositions containing varying amounts of water. The invention includes all these solvates.

The person skilled in the art will further appreciate that some compounds of formula I or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the different solvates thereof, may exhibit polymorphism (ie, the ability to present in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition, but differ in packaging, geometric arrangement and other descriptive properties of the crystalline solid state. Thus, polymorphs can have different physical properties, such as shape, density, hardness, deformability, stability and dissolution properties. The polymorphs typically show different melting points, IR spectra and X-ray powder diffraction patterns, which can be used for identification. The person skilled in the art will appreciate that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents, used in the preparation of the compound. For example, changes in temperature, pressure, or solvent, can result in polymorphs. In addition, under certain conditions a polymorph can spontaneously convert to another polymorph. The invention includes all these polymorphs.

Definitions The term "alkyl" refers to a hydrocarbon chain having the number of member atoms that is specified. For example, C 1 -C 4 alkyl refers to an alkyl group having from 1 to 4 member atoms. The alkyl groups can be saturated, unsaturated, linear or branched. Branched, representative alkyl groups have one, two or three branches. Alkyl includes methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene and butyl (n-butyl, isobutyl and t-butyl).

The term "alkoxy" refers to an -O-alkyl group in which "alkyl" is as defined herein. For example, C1-C4 alkoxy refers to an alkoxy group having 1 to 4 member atoms. Representative branched alkoxy groups have one, two or three branches. Examples of such groups include methoxy, ethoxy, propoxy and butoxy.

The term "aryl" refers to an aromatic hydrocarbon ring. The aryl groups are monocyclic ring systems or bicyclic ring systems. Examples of such monocyclic aryl rings include phenyl and biphenyl. Examples of such bicyclic aryl rings include naphthalene and rings in which the phenyl is fused with a cycloalkyl or cycloalkenyl ring having 5, 6 or 7 member atoms, for example tetrahydronaphthalene.

The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon ring having the specified number of member atoms Cycloalkyl groups are monocyclic ring systems For example, C3-C7 cycloalkyl refers to a cycloalkyl group having 3 to 7 member atoms Examples of cycloalkyl as used herein include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term "halogen" refers to the halogen fluoro, chloro, bromo and iodo radicals.

The term "heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups are monocyclic ring systems. The monocyclic heteroaryl rings have 5 or 6 member atoms. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl.

The term "heterocycloalkyl" refers to a saturated or unsaturated ring containing 1 to 4 heteroatoms as member atoms in the ring. Nevertheless, the heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring or with a heteroaryl ring having from 4 to 11 member atoms. In some embodiments, the heterocycloalkyl is saturated. In other embodiments, the heterocycloalkyl is unsaturated, but is not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathyanyl, 1,3-dithyanyl, 1,3-oxazolidin-2-one, hexahydro-1 H-azepine, 4,5,6,7, tetrahydro-1 H-benzimidazole, piperidinyl, 1, 2,3,6-tetrahydro- pyridinyl and azetidinyl. Suitably "heterocycloalkyl" includes: oxetanyl.

The term "bicycloheteroaryl" refers to two fused aromatic rings containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. The bicycloheteroaryl rings have from 6 to 11 member atoms. The bicycloheteroaryl includes: 1 H-pyrrolo [3,2-c] pyridine, 1 H-pyrazolo [4,3-c] pihdine, 1 H-pyrazolo [3,4-d] pyrimidine, 1 H-pyrrolo [ 2,3-djpyrimidine, 7H-pyrrolo [2,3-d] pyrimidine, thieno [3,2-c] pyridine, thieno [2,3-d] pyrimidine, furo [2,3-c] pyridine, furo [2,3-d] pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo [4.5-c] pyridine, imidazo [4,5-b] pyridine, furopyridinyl and naphthyridinyl.

The term "bicycloheteroaryl" suitably refers to two fused aromatic rings containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. The bicycloheteroaryl rings have from 6 to 11 member atoms. The bicycloheteroaryl includes: 1 H-pyrazolo [3,4-d] pyrimidine, 1 H-pyrrolo [2,3-d] pyrimidine, 7 H -pyrrolo [2,3-d] pyrimidine, thieno [3,2-c] pyridine, thieno [2,3-d] pyrimidine, furo [2,3-c] pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo [4,5-c] pyridine, imidazo [4,5-b] pyridine, furopyridinyl and naphthyridinyl.

The "bicycloheteroaryl" suitably includes: 1 H-pyrazolo [3,4-d] pyrimidine, 1 H-pyrrolo [2,3-d] pyrimidine, 7 H -pyrrolo [2,3-d] pyrimidine, thieno [3,2 -c] pyridine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinolinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo [4.5-c ] pyridine, imidazo [4,5-b] pyridine, furopyridinyl and naphthyridinyl.

The term "heteroatom" refers to a nitrogen, sulfur or oxygen atom.

"Pharmaceutically acceptable" refers to those compounds, materials, compositions and dosage forms that are, within the scope of the well-founded medical opinion, suitable for use in contact with the tissues of humans and animals, without excessive toxicity, irritation , or another problem or complication and that have a reasonable benefit / risk ratio.

As used herein, the symbols and conventions used in these procedures, schemes and examples are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter abbreviations are usually used of three letters to designate the amino acid residues, which are considered to be in the L configuration, unless otherwise indicated. Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, in the examples and throughout the specification, the following abbreviations may be used: Ac (acetyl); Ac20 (acetic anhydride); ACN (acetonitrile); AIBN (azobis (isobutyronitrile)); ATP (adenosine triphosphate); Bis- (pinacolato) diboro (4,4,4,, 4,, 5,5,5 ', 5, -Octamethyl-2,2'-bi-1, 3,2-dioxaborolane); BSA (bovine serum albumin); BINAP (2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl); BMS (borane-dimethylsulfoxide complex); Bn (benzyl); Boc (tert-Butoxycarbonyl); Boc20 (di-tert-butyl dicarbonate); BOP (Benzotriazol-1-yl-oxy-tris- (dimethylamine) -phosphonium hexafluorophosphate); C18 (refers to alkyl groups of 18 carbons on silicon in the stationary phase in HPLC); CH3CN (acetonitrile); Cy (cyclohexyl); CAN (calcareous ammonium nitrate); Cbz (benzyloxycarbonyl); CSI (chlorosulfonyl isocyanate); DABCO (1,4-Diazabicyclo [2.2.2] octane); DAST (Trifluoride of (diethylamino) sulfur); DBU (1,8-Diazabicyclo [5.4.0] undec-7-ene); DCC (Dicyclohexylcarbodiimide); DCE (1,2-dichloroethane); DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone); DCM (dichloromethane); DIEA (Hünig base, diisopropylethylamine, N-ethyl-N- (1-methylethyl) -2-propanamine); DIPEA (Hünig's base, diisopropylethylamine, N-ethyl-N- (l-methylethyl) 2-propanamine); DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF (N, N-dimethylformamide); DMSO (dimethylsulfoxide); DPPA (diphenylphosphorylazide); EDC (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); AcOEt (ethyl acetate); EtOH (ethanol); EÍ2Ü (diethyl ether); HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid); HATU (O - ^ - azabenzotriazol-l-iO-NN.N'.N'-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole); HOBt (1-hydroxybenzotriazole); HOAc (acetic acid); HPLC (high resolution liquid chromatography); HMDS (hexamethyldisilazide); Hunig base (?,? - Diisopropylethylamine); IPA (isopropyl alcohol); Indoline (2,3-dihydro-1 H-indole); KHMDS (potassium hexamethyldisilazide); LAH (lithium aluminum hydride); LDA (lithium düsopropylamide); LHMDS (lithium hexamethyldisilazide) MeOH (methanol); MTBE (tere-butyl ether and methyl); mCPBA (m-chloroperbezoic acid); NaHMDS (sodium hexamethyldisilazide) NBS (N-bromosuccinimide); PE (petroleum ether); Pd2 (dba) 3 (Tris (dibenzylideneacetone) dipalladium (O)); Pd (dppf) CI2 ([1, 1 '-Bi (diphenylphosphino) ferrocene] dichloropalladium (II)); PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate); RPHPLC (reverse phase high pressure liquid chromatography); RuPhos (2-Dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl); SFC (supercritical fluid chromatography); SGC (chromatography on silica gel); T3P® (propanephosphonic acid anhydride); TEA (triethylamine); TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl, free radical); TFA (trifluoroacetic acid); Y THF (tetrahydrofuran) Each time "ether" is mentioned it means diethyl ether and "brine" means a saturated aqueous solution of NaCl.

Preparation of Compounds The compounds according to formula I are prepared using conventional organic synthesis methods. The following is a suitable synthetic route in the following general reaction schemes.

The person skilled in the art will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent can be protected with a suitable protecting group, which is stable under the reaction conditions. The protecting group can be removed at a suitable point within the sequence of reactions, to provide a desired intermediate or target compound. Suitable protecting groups, and methods for protecting and deprotecting different substituents by employing such suitable protecting groups, are well known to those skilled in the art, and examples of them can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd edition), John Wiley & Sons, NY (1999). In some cases a substituent can be specifically selected to be reactive under the reaction conditions employed. Under these circumstances, the reaction conditions convert the selected substituent into another substituent which is either useful as an intermediate or is a desired substituent on an objective compound.

As indicated in scheme 1, the commercially available 5-bromoindoline 1 is acylated with a carboxylic acid using a coupling reagent (eg EDC, DCC or HATU) to form the amide bond at 2. The conversion of 2 in the boronate ester and the subsequent coupling of Suzuki-Miyaura provide the product 3. The boronate ester (represented by 4) can be purified and isolated if desired and subjected to the Suzuki-Miyaura coupling in a different synthetic procedure. The bicycloheteroaryl halides A and B are known compounds or are easily prepared by established methods.

SCHEME 1 n, (Suzuki-Miyaura link) Alternatively, the compounds of the invention can be prepared as indicated in scheme 2. The nitrogen of 5-bromoindoline 1 can be protected with the tert-butylcarbamate (Boc) group. The transformation to the heteroaryl-substituted indoline 6 is carried out as in Scheme 1, with or without isolating the intermediate boronate ester. Deprotection of the Boc group with HCI provides indoline 7, which can be converted to 3 using a coupling reagent (eg EDC, DCC or HATU) to form the amide bond.

SCHEME 2 , (link of SuziJd-iyaira) ulo Examples of the invention containing a 2-aminopyridine ring as part of the bicyclic heteroaryl group can be further substituted as indicated in scheme 3. The aminopyridine ring in a compound such as 8 can be iodinated to give 9, which after it can be further manipulated by conventional methods such as a transition metal-mediated coupling reaction to give a variety of R substituents such as aryl or alkyl groups.

SCHEME 3 X = C, N Y = S, O, NH, N-alkyl R = Ar, alkyl, halogen Examples of the invention with iodazole and 1 H-pyrazolo [3,4-c] pyridin-3-amine groups as R 1, represented by 15 can be prepared according to scheme 4. The borate 4 ester is it can be coupled under conditions of Suzuki- iyaura with 1 1 or 13, to provide compounds 12 and 14, respectively. The fluoronitrile 12 or chloronitrile of pyridine 14 can be reacted with hydrazine or an alkylhydrazine to effect the delation and formation of the bicycloheteroaryl groups indazole or 1 H-pyrazolo [3,4-c] pyridin-3-amine in 15.

SCHEME 4 The compounds of the invention containing a R1 bicycloheteroaryl furo [2,3-d] pyrimidin-4-amine group can be synthesized as indicated in Scheme 5. Starting with 1,5-diacetyl-indoline 16, the bromination followed displacement with sodium acetate and then basic hydrolysis provides the hydroxylketone 17, which when reacted with malononitrile in the presence of diethylamine provides the furan 18. The reaction of 18 with bis (ethyloxy) methyl acetate to prepare 19, followed by treatment of 19 with ammonia in methanol provides intermediate 20. Acetamide can be hydrolyzed with base to provide indoline 21, which when reacted under suitable conditions with an aryl or heteroaryl derivative of acetic acid, provides the compounds of the invention with general structure 22.

SCHEME 5 Methods of use The compounds according to formula I and the pharmaceutically acceptable salts thereof are inhibitors of PERK. These compounds are potentially useful in the treatment of conditions in which the underlying pathology can be attributed (but not limited to) to the activation of the UPR pathway, for example, cancer and more specifically cancers of the breast, colon and lung. , pancreas and skin. Accordingly, another aspect of the invention relates to methods for treating said conditions.

Suitably, the present invention relates to a method for treating or reducing the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma and lobular carcinoma.

Suitably, the present invention relates to a method for treating or reducing the severity of colon cancer.

Suitably, the present invention relates to a method for treating or reducing the severity of pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma and glucagonoma.

Suitably, the present invention relates to a method for treating or reducing the severity of skin cancer, including melanoma and metastatic melanoma.

Suitably, the present invention relates to a method for treating or reducing the severity of lung cancer, including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma and large cell carcinoma.

Suitably, the present invention relates to a method for treating or reducing the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreatic, adenocarcinoma, ductal adenocarcinoma , adenosquamous carcinoma, achary cell carcinoma, glucagonoma, insulin, prostate, sarcoma, osteosarcoma, giant cell tumor, thyroid, lymphoblastic leukemia of T lymphocytes, chronic mileoid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, T lymphoblastic leukemia, plasmacytoma, large cell immunoblastic leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, lymphoma of hodgkins, non-hodgkins lymphoma, lymph T lymphoblastic lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, cancer of the salivary glands, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

Suitably, the present invention relates to a method for treating or reducing the severity of precancerous syndromes in a mammal, including a human being, in which the precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammopathy of undetermined significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin moles (pre-melanoma), intraepithelial prosthetic neoplasia (intraductal) (PIN), ductal carcinoma in situ ( DCIS), colon polyps and severe hepatitis or cirrhosis.

Suitably, the present invention relates to a method for treating or reducing the severity of additional diseases associated with UPR activation that include: type 1 diabetes, Alzheimer's disease, stroke, Parkinson's disease, Huntington's disease, sclerosis Amyotrophic lateral, myocardial infarction, cardiovascular disease, atherosclerosis and arrhythmias.

The compounds of this invention inhibit angiogenesis which is involved in the treatment of ocular diseases. Nature Reviews Drug Discovery 4, 71 1-712 (September 2005). Suitably, the present invention relates to a method for treating or reducing the severity of eye diseases / angiogenesis. In embodiments of methods according to the invention, the eye disease disorder, including vascular effusions, may be: edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as iris rubeosis, neovascular glaucoma, pterygium, glaucoma filter blisters vascularized, papilloma of the conjunctiva; choroidal neovascularization, such as neovascular age-associated macular degeneration (AMD), myopia, anterior, traumatic, or idiopathic uveitis; macular edema, such as edema post-surgical macular, macular edema secondary to uveitis including retinal and / or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to occlusive retinovascular disease (ie, occlusion of the central vein and venous branch of the retina); retinal neovascularization due to diabetes, such as retinal venous occlusion, uveitis, ocular ischemia syndrome due to carotid artery disease, ophthalmic or retinal arterial occlusion, sickle cell retinopathy, other occlusive or ischemic neovascular retinopathies, retinopathy of prematurity, or Eales; and genetic disorders, such as VonHippel-Lindau syndrome.

In some embodiments, macular degeneration associated with neovascular age is wet macular degeneration associated with age. In other embodiments, the macular degeneration associated with neovascular age is dry macular degeneration associated with age and the patient is characterized as having a greater risk of developing wet macular degeneration associated with age.

The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula I or one of its pharmaceutically acceptable salts, to a patient in need thereof.

The invention also provides a compound according to formula I or a pharmaceutically acceptable salt thereof, for use in medical therapy, and in particular in cancer therapy. Therefore, in a further aspect, the invention is directed to the use of a compound in accordance with the formula I or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disorder characterized by the activation of the UPR, such as cancer.

By the term "treatment" and derivatives thereof, as used herein, is meant prophylactic and therapeutic therapy. Prophylactic therapy is appropriate, for example, when a subject is considered to be at high risk of developing cancer, or when a subject has been exposed to a carcinogen.

As used herein, the term "effective amount" and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human being that seeks, for example. , a researcher or doctor. In addition, the term "therapeutically effective amount" and derivatives thereof means any amount which, compared to a corresponding subject who has not received said amount, results in an improved treatment, cure, prevention or improvement of a disease, disorder or effect. secondary, or a decrease in the rate of progression of a disease or disorder. The expression also includes in its scope effective amounts to improve normal physiological function.

As used herein, "patient" or "subject" refers to a human being or other animal. Suitably, the patient or subject is a human being.

Compounds of Formula lo the pharmaceutically salts acceptable thereof can be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration and parenteral administration. Parenteral administration refers to routes of administration other than enteric, transdermal or inhalation, and is typically performed by injection or infusion. Parenteral administration includes intravenous, intramuscular injection, and intraperitoneal and subcutaneous injection or infusion.

The compounds of formula I or the pharmaceutically acceptable salts thereof can be administered once or according to a dosage regimen in which a series of doses are administered at varying intervals of time for a given period of time. For example, doses can be administered once, twice, three or four times a day. The doses can be administered until the desired therapeutic effect is obtained or indefinitely to maintain the desired therapeutic effect. Suitable dosage regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half-life, which can be determined by the person skilled in the art. In addition, suitable dosage regimens, including the duration in which such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient concerned, the medical history of the patient in question, the nature of the therapy concurrent, the desired therapeutic effect, and similar factors that are within the expert's knowledge and experience. In addition, those skilled in the art will understand that suitable dosing regimens may require adjustments depending on the individual response of the patient to the dosing regimen or with the passage of time when the individual patient needs a change.

In addition, the compounds of formula I or pharmaceutically acceptable salts thereof can be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound that, when administered to a patient, eventually releases the compound of the invention in vivo. The administration of a compound of the invention in the form of a prodrug may allow one skilled in the art to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modifying the duration of the action of the compound in vivo; (c) modify the transport or distribution of the compound in vivo; (d) modifying the solubility of the compound in vivo; and (e) overcoming a side effect or other difficulty encountered with the compound. When a -COOH or -OH group is present, pharmaceutically acceptable esters, for example methyl, ethyl, and the like can be used for -COOH, and acetate, maleate and the like for -OH, and esters known in the art to modify the solubility or hydrolysis characteristics.

The compounds of formula I and pharmaceutically salts acceptable therefrom, they can be co-administered with at least one other active agent known to be useful in the treatment of cancer.

By the term "co-administration" as used herein, is meant the simultaneous administration or any form of separate sequential administration of a PERK inhibitor compound, as described herein, and an active agent or agents additional, which are known to be useful in the treatment of cancer, including the treatment of chemotherapy and radiation. The term "additional active agent or agents", as used herein, includes any compound or therapeutic agent known to or demonstrating advantageous properties when administered to a patient in need of treatment for a cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close-to-time manner. Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound can be administered by injection and another compound can be administered orally.

Typically, in the cancer treatment of the present invention, any antineoplastic agent having activity against a susceptible tumor that is being treated can be coadministered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 5, 2001), Lippincott Williams & Wilkins Publishers. One skilled in the art could determine the combinations of agents that would be useful based on the particular characteristics of the drugs and the cancer involved. Typical antineoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogs and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; Hormones and hormone analogues; inhibitors of the signal transduction pathway; inhibitors of tyrosine kinase angiogenesis not associated with receptors; immunotherapeutic agents; proapoptotic agents; inhibitors of cell cycle signaling; proteasome inhibitors; and inhibitors of cancer metabolism.

Examples of an additional active principle or principles (anti-neoplastic agent) for use in combination or co-administration with the PERK inhibitor compounds of the present invention are the chemotherapeutic agents.

Anti-microtubule or antimitotic agents are agents with phase specificity active against the microtubules of tumor cells during the M phase or mitosis of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

The diterpenoids, which come from natural sources, are anti-cancer agents with phase specificity that act in the G2 / M phases of the cell cycle. It is believed that diterpenoids stabilize the β-tubulin subunit of microtubules, by binding to this protein. Then, it seems that the disassembly of the protein is inhibited, halting the mitosis and subsequently producing cell death. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogue docetaxel.

Paclitaxel, 13-ester of 4,10-diacetate 2-benzoate 5β, 20-epo i-1, 2a, 4,7β, 10β, 13a-hexa-hydroxylax-1 1-en-9-one with (2R , 3S) -N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew Taxus brevifolia and available commercially as a TAXOL® injectable solution. It is a member of the terpene family that is called taxanes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc, 93: 2325, 1971), which characterized its structure by chemical methods and X-ray crystallography. One mechanism for its activity refers to the ability of paclitaxel to bind to tubulin, inhibiting this way the growth of cancer cells. Schiff et al., Proc. Nati, Acad, Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). As a review of the synthesis and anticancer activity of some paclitaxel derivatives see: D. G. I. Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pages 219-235.

Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intem, Med. , 1 1: 273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991). It is a potential candidate for the treatment of neoplasms in the skin (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46) and carcinomas of the head and neck (Forastire et al., Sem. Oncol. ., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750, 1994), lung cancer and malaria. The treatment of patients with paclitaxel represses the bone marrow (multiple cell lineages, Ignoff, RJ et al., Cancer Chemotherapy Pocket GuideA 1998) in a way related to the duration of the dosage above a limit concentration (50 nM) (Kearns, CM et al., Seminars in Oncology, 3 (6) p.16-23, 1995).

The docetaxel, 13-ester, N-fer-butyl ester of (2R, 3S) -N-carboxy-3-phenylisoserine with 4-acetate 2-benzoate of 5β-20-β-1, 2a, 4,7p, 10p, 13a-hexahydroxitax-1 1-en-9-one, trihydrate; It is available in the market as an injectable solution called TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-desacetyl-baccatin III, extracted from the needles of the European yew. The dose-limiting toxicity of docetaxel is neutropenia.

The vinca alkaloids are antineoplastic agents with phase specificity derived from the periwinkle plant. The vinca alkaloids act in the M phase (mitosis) of the cell cycle by means of their specific binding to tubulin. Accordingly, the bound tubulin molecule can not polymerize to form microtubules. It is believed that mitosis stops in the metaphase, causing cell death later on. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.

Vinblastine, vincaleucoblastine sulfate, is available on the market under the name VELBAN®, as an injectable solution. Although it has a possible indication as a second-line therapy of various solid tumors, it is mainly indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose-limiting side effect of vinblastine.

Vincristine, vincaleucoblastine, 22-oxo-, sulfate, is available on the market with the name ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found utility in treatment regimens for malignant Hodgkin and non-Hodgkin lymphomas. The most common side effects of vincristine are alopecia and neurological effects and, to a lesser extent, myelosuppressive effects and gastrointestinal mucositis occur.

Vinorelbine, 3 ', 4'-didehydro-4'-deoxy-C'-norvincaleucoblastin [R- (R *, R *) - 2,3-dihydroxybutanedioate (1: 2) (salt)], commercially available As an injectable solution of vinorelbine tartrate (NAVELBINE®), it is a semi-synthetic vinca alkaloid. Vinorelbine is indicated, as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-microcytic lung cancers, advanced breast cancer and hormone-refractory prostate cancer. Myelosuppression is the limiting side effect of the most common dose of vinorelbine.

Platinum coordination complexes are non-phase-specific cancer agents that interact with DNA. The platinum complexes enter the tumor cells, undergo hydration and form intra- and inter-chain cross-links with the DNA, causing adverse biological effects on the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin, cis-diaminadichloroplatinum, is available commercially under the name PLATINOL® as an injectable solution. Cisplatin is indicated primarily in the treatment of testicular and ovarian metastatic cancer and in advanced bladder cancer. The main dose-limiting side effects of cisplatin are nephrotoxicity, which can be controlled by hydration and diuresis, and ototoxicity.

The carboplatin, diamine [1,1-cyclobutane-dicarboxylate (2 -) - 0.0 '] of platinum, is available commercially under the name PARAPLATIN® as an injectable solution. Carboplatin is indicated primarily in the first and second line treatment of advanced ovarian carcinoma. The limiting toxicity of the carboplatin dose is bone marrow depression.

Alkylating agents are anti-cancer agents without phase specificity and are strong electrophiles. Typically, the alkylating agents form covalent bonds, by alkylation, with the DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups. This alkylation alters the function of the nucleic acid producing cell death. Examples of alkylating agents include, but are not limited to, nitrogenous mustards such as cyclophosphamide, melphalan and chlorambucil; alkylsulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2- [bis (2-chloroethyl) amino] tetrahydro-2H-1 2-oxide, 3,2-oxazaphosphorine monohydrate, is commercially available as an injectable solution or as tablets with the name CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma and leukemias. The most common dose-limiting side effects of cyclophosphamide are alopecia, nausea, vomiting and leukopenia.

Mallflan, 4- [bis (2-chloroethyl) amino] -L-phenollanine, is commercially available as an injectable solution or tablets with the name ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow depression is the limiting side effect of the most common dose of melphalan.

Chlorambucil, 4- [bis (2-chloroethyl) amino] benzenebutanoic acid, is commercially available as tablets with the name LEUKERAN®. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and for malignant lymphomas such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease. Bone marrow depression is the limiting side effect of the most common dose of chlorambucil.

Busulfan, dimethanesulfonate, 4-butanediol, is available commercially as tablets with the name MYLERANn. Busulfan is indicated for the palliative treatment of chronic myeloid leukemia. Bone marrow depression is the limiting side effect of the most common dose of busulfan.

Carmustine, 1, 3- [bis (2-chloroethyl) -1-nitrosourea, is commercially available as individual vials of lyophilized material under the name BiCNU®. Carmustine is indicated for palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin lymphomas. The Delayed myelosuppression is the limiting side effect of the most common dose of carmustine.

Dacarbazine, 5- (3,3-dimethyl-1-triazene) -imidazole-4-carboxamide, is available in the market as individual vials of material with the name DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second-line treatment of Hodgkin's disease.

Nausea, vomiting and anorexia are the most common dose limiting side effects of dacarbazine.

Antineoplastic antibiotics are agents without phase specificity, which bind or intercalate with DNA. Typically, this action produces stable DNA complexes or chain breaks, which alter the normal function of nucleic acids causing cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins, such as dactinomycin, anthracyclines such as daunorubicin and doxorubicin; and bleomycins.

Dactinomycin, also known as Actinomycin D, is commercially available in an injectable formulation with the name COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis -) - 8-acetyl-10 - [(3-amino-2,3,6-trideoxy-L-lixo-hexopyranosyl) oxy] -7,8,9,10- hydrochloride tetrahydro-6,8,1-trihydroxy-1-methoxy-5,12-naphtacenedione, is available commercially as a liposomal injectable formulation under the name DAUNOXOME® or as an injectable under the name CERUBIDINE®. Daunorubicin is indicated for the induction of remission in the treatment of acute non-lymphocytic leukemia and Kaposi's sarcoma associated with advanced HIV. Myelosuppression is the limiting side effect of the most common dose of daunorubicin.

Doxorubicin, (8S, 10S) -10 - [(3-amino-2,3,6-trideoxy-aL-lixo-hexopyranosyl) oxy] -8-glycolyl hydrochloride, 7,8,9, 10-tetrahydrochloride 6, 8,11 -trihydroxy-1-methoxy-5, 12-naphtacenedione is commercially available as an injectable formulation with the name RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is indicated mainly for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the limiting side effect of the most common dose of doxorubicin. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas and testicular carcinomas. Pulmonary and cutaneous toxicities are the side effects limiting the most common dose of bleomycin.

Topoisomerase II inhibitors include, but are not limitation, epipodophyllotoxins.

Epipodophyllotoxins are antineoplastic agents with phase specificity derived from the mandrake plant. Epipodophyllotoxins typically affect cells in S and G? of the cell cycle forming a ternary complex with topoisomerase II and DNA causing breaks in the DNA strands. The breaks of the chains accumulate and subsequently cell death occurs. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -ethylidene-β-D-glucopyranoside], is commercially available as an injectable solution or capsules under the name VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of testicular cancer and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenia tends to be more severe than thrombocytopenia.

Teniposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0- (R) -tenylidene-pD-glucopyranoside], is commercially available as an injectable solution with the name VUMON® and is commonly referred to as VM-26 . Teniposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia in children. Myelosuppression is the limiting side effect of the most common dose of teniposide. Teniposide can induce both leukopenia and thrombocytopenia.

Neoplastic antimetabolite agents are antineoplastic agents with phase specificity that act in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting the synthesis of purine or pyrimidine bases , thus limiting the synthesis of DNA. Therefore, phase S does not continue and cell death occurs. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecarptopurine, thioguanine, and gemcitabine. 5-Fluorouracil, 5-fluoro-2,4- (1 H, 3H) -pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to the inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are side effects limiting the dose of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro-deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-p-D-arabinofuranosyl-2 (1 H) -pyrimidinone, is commercially available under the name CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity in the S phase by inhibiting the elongation of the DNA strand by terminal incorporation of cytarabine into the growing DNA strand. Cytarabine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2 ', 2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. The mercaptopurine presents specificity of cellular phase in the S phase by means of the inhibition of the synthesis of DNA by a mechanism not specified until now. Mercaptopurine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analogue is azathioprine.

Thioguanine, 2-amino-1, 7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine presents specificity of cellular phase in the S phase by means of the inhibition of the synthesis of DNA by a mechanism not specified until now. Thioguanine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Myelosuppression, including leukopenia, thrombocytopenia and anemia, is the limiting side effect of the most common dose of thioguanine administration. However, gastrointestinal side effects appear and can be dose-limiting. Other purine analogues include pentostatin, erythrohydroxyinilaydenine, fludarabine phosphate and cladribine.

Gemcitabine, 2'-deoxy-2 ', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity in the S phase by blocking the progression of cells along the G1 / S limit. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and individually in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leukopenia, thrombocytopenia and anemia, is the limiting side effect of the most common dose of gemcitabine administration.

Methotrexate, N- [4 - [[(2,4-diamino-6-pteridinyl) methyl] methylamino] benzoyl] -L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate presents effects of cellular phase specifically in the S phase by means of the inhibition of the synthesis, repair and / or replication of DNA through the inhibition of the dihydrofolic reductase acid that is required for the synthesis of purine and thymidylate nucleotides . Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary, and bladder. Myelosuppression (leukopenia, thrombocytopenia and anemia) and mucositis are expected side effects of methotrexate administration.

Camptothecins, including camptothecin and camptothecin derivatives, are available or are in development as inhibitors of Topoisomerase I. It is believed that the cytotoxic activity of camptothecins is related to their inhibitory activity on Topoisomerase I. Examples of camptothecins include, but without limitation, irinotecan, topotecan and the various optical forms of 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20-camptothecin described below.

Irinotecan HCl, (4S) -4,1 1 -diethyl-4-hydroxy-9 - [(4-piperidinopiperidino) carbonyloxy] -1H-pyrano [3 ', 4', 6,7] indolizino hydrochloride [1 , 2-b] quinoline-3,14 (4H, 12H) -dione, is commercially available as the injectable solution CAMPTOSAR®.

Irinotecan is a camptothecin derivative that binds, together with its active metabolite SN-38, to the topoisomerase I-DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double chain breaks caused by the interaction of topoisomerase I: DNA: irinotecan or the ternary complex SN-38 with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. The dose-limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and Gl effects, including diarrhea.

Topotecan HCI, (S) -10 - [(dimethylamino) methyl] -4-ethyl-4,9-dihydroxy-1 H-pyran [3 ', 4', 6,7] indolizine monohydrochloride [1, 2 b] quinoline-3, 14- (4H, 12H) -dione, is available in the market as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex and prevents the religation of single strand breaks produced by Topoisomerase I in response to a twisting strain of the DNA molecule. Topotecan is indicated for the second-line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose-limiting side effect of HCI topotecan is myelosuppression, mainly neutropenia.

Also of interest is the camptothecin derivative of the formula A shown below, including the racemic mixture (R, S) as well as the R and S enantiomers: known by the chemical name "7- (4-methylpiperazino-methylene) -10,1 1-ethylenedioxy-20 (R, S) -camptothecin (racemic mixture) or" 7- (4-methylpiperazino-methylene) -10, 1 1-ethylenedioxy-20 (R) -camptothecin (R-enantiomer) or "7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20 (S) -camptothecin (S-enantiomer) .These compounds, as well as the compounds Related, are described, including methods for their manufacture, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; 5,491,237 and in U.S. Patent Application No. 08 / 977,217 filed the November 24, 1997.

Certain hormones and hormone analogues are useful compounds for treating cancers, in which there is a relationship between the hormones and the growth and / or absence of cancer growth. Examples of hormones and hormone analogs useful in the treatment of cancers include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphomas and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole and exemestane useful in the treatment of adrenocortical carcinoma and hormone-dependent breast carcinoma containing estrogen receptors; progestins such as megestrol acetate useful in the treatment of hormone-dependent breast cancer and endometrial carcinoma; estrogens, androgens and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, as well as selective estrogen receptor modulators (SERMS) such as those described in U.S. Patent Nos. 5,681,835, 5,877,219 and 6,207,716, useful in the treatment of breast carcinomas dependent on hormones and other susceptible cancers; and gonadotropin releasing hormone (GnRH) and analogs thereof that stimulate the release of luteinizing hormone (LH) and / or follicle stimulating hormone (FSH) for the treatment of prostate carcinoma, for example, agonists and antagonists of LHRH such as goserelin acetate and leuprolide.

Inhibitors of the signal transduction pathway are inhibitors that block or inhibit a chemical process that causes an intracellular change. As used herein, this change is cell proliferation or differentiation. Inhibitors of signal transduction useful in the present invention include receptor-associated tyrosine kinase inhibitors, tyrosine kinases not associated with receptors, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinases, myocardial signaling. inositol and Ras oncogenes.

Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. These protein tyrosine kinases can be classified broadly as kinases associated with receptors and not associated with receptors.

Tyrosine kinases associated with receptors are transmembrane proteins that have an extracellular ligand binding domain, a transmembrane domain and a tyrosine kinase domain. Tyrosine kinases associated with receptors are involved in the regulation of cell growth and are generally referred to as growth factor receptors. It has been shown that an inappropriate or uncontrolled activation of many of these kinases, that is, an aberrant activity of a kinase growth factor receptor, for example, by overexpression or mutation, results in uncontrolled cell growth. Accordingly, the aberrant activity of these kinases has been associated with malignant tissue growth. Accordingly, inhibitors of these kinases could provide methods of treating cancers. Growth factor receptors include, for example, the epidermal growth factor receptor (EGFr), the platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, the vascular endothelial-derived growth factor receptor ( VEGFr), tyrosine kinase with immunoglobulin-like domains and homology to epidermal growth factor (TIE-2), insulin-like growth factor-l (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK , ckit, cmet, fibroblast growth factor receptors (FGF), Trk receptors (TrkA, TrkB, and TrkC), ephrin receptors (eph) and the RET protooncogene. Several inhibitors of growth receptors are in development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10 (6): 803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5 - [[4 - [(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably its monohydrochloride salt, which is described and claimed in the application of international application number PCT / US01 / 49367, which has an international filing date of 19 December, 2001, international publication number WO02 / 0591 10 and an international publication date of August 1, 2002, the entire description of which is incorporated herein by reference, and which is the compound of example 69. The 5- [ [4 - [(2,3-dimethyl-2 H -ndazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide can be prepared as described in international application No. PCT / US01 / 49367 .

Suitably, 5 - [[4 - [(2,3-dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide is in the form of a monohydrochloride salt. This form of salt can be prepared by the person skilled in the art from the description in international application No. PCT / US01 / 49367, which has an international filing date of December 19, 2001. 5 - [[4 - [(2,3-Dimethyl-2H-indazol-6-yl) methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide is commercially available as the monohydrochloride salt and is knows with the generic name of pazopanib and the commercial name Votrient®.

Pazopanib is involved in the treatment of cancer and eye diseases / angiogenesis. Suitably, the present invention relates to the treatment of cancer and eye diseases / angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of formula (I) alone or in combination with pazopanib.

Tyrosine kinases that are not kinases associated with growth factor receptors are called tyrosine kinases not associated with receptors. Tyrosine kinases not associated with receptors for use in the present invention, which are potential targets or targets of anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase and Bcr -Abl. These kinases not associated with receptors and agents that inhibit the tyrosine kinase function are described in non-associated receptors in Sinh, S. and Corey, S.J., (1999) Journal of Hematology and Stem Cell Research 8 (5): 465-80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371-404.

Blockers of the SH2 / SH3 domain are agents that prevent the binding of the SH2 or SH3 domain to a variety of enzymes or adapter proteins including the p85 subunit of PI3-K, kinases of the Src family, adapter molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. SH2 / SH3 domains are described as targets for anti-cancer drugs in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34 (3) 125-32.

Serine / threonine kinase inhibitors including MAP kinase cascade blockers that include Raf kinase blockers (rafk), mitogen-regulated kinase or extracellular signals (MEK) and kinases regulated by extracellular signals (ERK); and blockers of members of the protein kinase C family including PKC blockers (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). Family of IkB kinases (IKKa, IKKb), kinases of the PKB family, members of the akt kinase family, kinases of the PDK1 and TGF beta receptors. These serine / threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60, 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41 -64; Philip, P.A., and Harris, A.L (1995), Cancer Treatment and Research. 78: 3-27 Lackey, K. et al., Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; Pearce, L.R et al. Nature Reviews Molecular Cell Biology (2010) 11, 9-22. and Martinez-lacaci, L, et al., Int. J. Cancer (2000), 88 (1), 44-52.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an MEK inhibitor. Properly, the N-. { 3- [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido [4 , 3-d] pyrimidin-1-yl] phenyl} acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethylsulfoxide solvate thereof, which is described and claimed in the international application PCT / JP2005 / 01 1082, which has an international filing date of June 10, 2005; international publication number WO 2005/121142 and an international publication date of December 22, 2005, the entire description of which is incorporated herein by reference. The N-. { 3- [3-cyclopropyl-5- (2-fluoro-4-iodo-phenylamino) -6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido [4 , 3-d] pyrimidin-1-yl] phenyl} acetamide, can be prepared as described in U.S. Patent Publication No. US 2006/0014768, published January 19, 2006, the entire disclosure of which is incorporated herein by reference.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Properly, the / V-. { 3- [5- (2-Amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is described and claimed in international application No. PCT / US2009 / 042682, which has an international filing date of May 4, 2009, the entire description of which it is incorporated herein by reference. The / V-. { 3- [5- (2-amino-4-pyrimidinyl) -2- (1,1-dimethylethyl) -1,3-thiazol-4-yl] -2-fluorophenyl} -2,6-difluorobenzenesulfonamide can be prepared as described in international application No. PCT / US2009 / 042682.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor.

Properly, the N-. { (1 S) -2-amino-1 - [(3,4-difluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-furancarboxamide or a pharmaceutically acceptable salt thereof, which is described and claimed in the international application No. PCT / US2008 / 053269, which has an international filing date of February 7, 2008; international publication number WO 2008/098104 and an international publication date of August 14, 2008, the entire description of which is incorporated herein by reference. The N-. { (1S) -2-amino-1 - [(3,4-difluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-furancarboxamide is the compound of example 224 and can be prepared as described in the international application No. PCT / US2008 / 053269.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Properly, the / V-. { (1 S) -2-amino-1 - [(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 / -pyrazol-5-yl) -2-thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is described and claimed in international application n ° PCT / US2008 / 053269, which has an international filing date of February 7, 2008; international publication number WO 2008/098104 and an international publication date of August 14, 2008, the entire description of which is incorporated herein by reference. The / V-. { (1 S) -2-amino-1 - [(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-thiophenecarboxamide is the compound of example 96 and can be prepared as described in the international application No. PCT / US2008 / 053269. Adequately, the A / -. { (1 S) -2-amino-1 - [(3-fluorophenyl) methyl] ethyl} -5-chloro-4- (4-chloro-1-methyl-1 H -pyrazol-5-yl) -2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by the person skilled in the art from the description in the international application No. PCT / US01 / 022323, which has an international filing date of January 28, 2010.

Inhibitors of the members of the phosphatidyl inositol-3 kinase family, including the PI3-kinase, ATM, DNA-PK and Ku blockers, may also be useful in the present invention. These kinases are described in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, CE., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H. et al, Cancer Res., (2000) 60 (6), 1541-1545, Also of interest in the present invention are inhibitors of myoinositol signaling such as phospholipase C blockers and myoinositol analogs. These signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of inhibitors of the signal transduction pathway are inhibitors of the Ras oncogene. These inhibitors include inhibitors of farnesyl transferase, geranyl-geranyl transferase, and CAAX proteases, as well as antisense oligonucleotides, ribozymes, and immunotherapy. It has been shown that these inhibitors block the activation of ras in cells containing the wild-type ras mutant, thus acting as anti-proliferation agents. The inhibition of the Ras oncogene is described in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.l. Matar, P. (2000), Journal of Biomedical Science. 7 (4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim. Biophys. Acta, (19899) 1423 (3): 19-30.

As mentioned above, antagonists of ligand-binding kinases associated with receptors can also serve as inhibitors of signal transduction. This group of inhibitors of the signal transduction pathway includes the use of humanized antibodies against the extracellular ligand binding domain of receptor-associated tyrosine kinases. For example, the specific antibody Imclone C225 EGFR (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); the Herceptin antibody? erbB2 (see Tyrosine Kinase Signaling in Breast CancerBB Family Receiver Tyrosine Kniases, Breast Cancer Res., 2000, 2 (3), 176-183); and the specific antibody 2CB VEGFR2 (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51-17-5124).

Inhibitors of angiogenesis, which are kinases not associated with receptors, may also be useful in the present invention. The related angiogenesis inhibitors VEGFR and TIE2 have been previously described in relation to inhibitors of signal transduction (the two receptors are tyrosine kinases associated with receptors). Angiogenesis in general is associated with erbB2 / EGFR signaling, since it has been shown that erbB2 and EGFR inhibitors inhibit angiogenesis, mainly the expression of VEGF. Accordingly, tyrosine kinase inhibitors not associated with receptors can be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies that do not recognize VEGFR (receptor-associated tyrosine kinase), but bind to the ligand may also be useful in combination with the disclosed compounds; small molecule integrin inhibitors (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK). (See Bruns CJ, et al. (2000), Cancer Res., 60: 2926-2935, Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L. et al. (2000), Oncogene 19: 3460-3469).

They may also be useful in combination with the compounds of formula (I) agents used in immunotherapeutic regimens. There are several immunological strategies to generate an immune response. These strategies are usually in the field of tumor vaccinations. The efficacy of immunological strategies can be greatly improved by means of the combined inhibition of signaling pathways using a small molecule inhibitor. A discussion of the immunological procedure / tumor vaccine against erbB2 / EGFR in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

In the combination of the present invention, agents used in proapoptotic regimens (eg, bcl-2 antisense oligonucleotides) can also be used. Certain members of the Bcl-2 family of proteins block apoptosis. Therefore, positive regulation of bcl-2 has been associated with chemoresistance. Studies have shown that epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (ie, mcl-1). Therefore, certain strategies designed to negatively regulate the expression of bcl-2 in tumors have been shown to have a beneficial clinical effect and are now in Phase II / III assays, particularly the antisense oligonucleotide G3 39 bcl-2 from Genta. These proapoptotic strategies are described using the antisense oligonucleotide strategy for bcl-2 in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

Inhibitors of cell cycle signaling inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins controls progression through the eukaryotic cell cycle. Coordinated activation and inactivation of different cyclin / CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signaling are in development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4 and CDK6 and inhibitors therefor, for example, in Rosania et al., Exp. Opin. Ther. Patents (2000) 10 (2): 215-230. In addition, p21WAF1 / CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds known to induce the expression of p21WAF1 / CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressor activity (Richon et al., Proc. Nat Acad. Sci. USA 97 (18): 10014-10019 (2000)), and are included as inhibitors of cell cycle signaling. Histone deacetylase inhibitors (HDACs) are involved in transcription activation of p21WAF1 / CIP1 (Vigushin et al., Anticancer Drugs, 13 (1): 1-13 (Jan 2002)), and are signaling inhibitors. of the cell cycle suitable for use in combination herein. Examples of said HDAC inhibitors include: 1 . Vorinostat, including its pharmaceutically acceptable salts. Marks et al., Nature Biotechnology 25, 84-90 (2007); Stenger, Community Oncology 4, 384-386 (2007).

The vorinostat has the following name and chemical structure: A / -hydroxy- / V-phenyl-octanod amide Romidepsin, including its pharmaceutically salts Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

Romidepsin has the following name and chemical structure: (1S, 4S, 7Z, 10S, 16E, 21R) -7-ethylidene-4,21-di (propan-2-yl) -2-oxa-12,13-dithia- 5,8,20,23- tetrazabicyclo [8.7.6] tricos-16-ene-3,6,9,19,22-pentona 3. Panobinostat, including its pharmaceutically acceptable salts. Drugs of the Future 32 (4): 315-322 (2007).

The panobinostat, has the following name and chemical structure: (2E) -A- -hydroxy-3- [4- ( { [2- (2-methyl-1 H -indol-3-yl) ethyl] amino.} Methyl) phenyl] acrylamide 4. Valproic acid, including its pharmaceutically acceptable salts. Gottlicher, et al., EMBO J. 20 (24): 6969-6978 (2001).

Valproic acid has the following name and chemical structure: 2-propylpentanoic acid 5. Mocetinostat (MGCD0103), including its pharmaceutically acceptable salts. Balasubramanian et al., Cancer Letters 280: 21 1 -221 (2009).

Mocetinostat has the following name and chemical structure: A / - (2-Aminophenyl) -4 - [[(4-pyridin-3-ylpyrimidin-2-yl) amino] methyl] benzamide Additional examples of HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-21 16, in particular the compounds of Table 3 thereof indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break proteins, such as p53 protein. Several proteasome inhibitors are marketed or are being studied in the treatment of cancer. Inhibitors of proteasomes suitable for use in combination herein include: 1. Bortezomib (Velcade®), including its pharmaceutically acceptable salts. Adams J., Kauffman M. (2004), Cancer Invest. 22 (2): 304-1 1.

Bortezomib has the following name and chemical structure: [(1 R) -3-Methyl-1 - ( { (2S) -3-phenyl-2 - [(pyrazin-2-ylcarbonyl) amino] propanoyl.] - amino) butyl] boronic acid 2. Disulfiram, including its pharmaceutically acceptable salts.

Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20. Disulfiram has the following name and chemical structure: 1, 1 ', 1", 1'" - [dissulfanodylbis (carbonothioyltin)] tetraethane 3. Epigallocatechin gallate (EGCG), including its pharmaceutically acceptable salts. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 1 8 (6): 1369-74.

Epigallocatechin gallate has the following name and chemical structure: 3,4,5-trihydroxybenzoate of [(2R, 3R) -5,7-dihydroxy-2- (3,4,5-thhydroxyphenyl) chroman-3-yl] 4. Salinosporamide A, including its pharmaceutically acceptable salts. Feling et al., (2003). Angew. Chem. Int. Ed. Engl. 42 (3): 355-7.

Salinosporamide A has the following name and chemical structure. (4R, 5S) -4- (2-Chloroetyl) -1 - ((1S) -cyclohex-2-enyl (hydroxy) methyl) -5-methyl-6-oxa-2-azab 'iciclo3.2.0heptano-3,7 * -dione 5. Carfilzomib, including pharmaceutically acceptable safeties. Kuhn D.J., et al., Blood, 2007, 1 10: 3281 -3290.

Carfilzomib has the following name and chemical structure.

(S) -4-methyl-N - ((S) -1 - (((S) -4-methyl-1 - ((R) -2-methyloxyran-2-yl) -1 -oxopentan-2-yl ) amino) -1 -oxo-3-phenylpropan-2-yl) -2 - ((S) -2- (2-morpholinoacetamido) -4- phenylbutanamido) pentanamide Heat shock proteins of 70 kilodalton (Hsp70s) and heat shock proteins of 90 (Hsp90s) are families of heat shock proteins expressed ubiquitously. Hsp70s and Hsp90s are expressed in excess in certain types of cancer. Several inhibitors of Hsp70s and Hsp90s have been studied in the treatment of cancer. Inhibitors of Hsp70s and Hsp90s suitable for use in combination in the present memory include: 1. 17-AAG (Geldanamycin), including its pharmaceutically acceptable salts. Jia W. et al. Blood. Sep 1 2003; 102 (5): 1824-32. 17-AAG (Geldanamycin) has the following name and chemical structure. 17- (Allylamino) -17-demethoxygeldanamycin 2. Radicicol, including its pharmaceutically acceptable salts. (Lee et al., Mol Cell Endocrinol, 2002, 188, 47-54) The radicicol has the following name and chemical structure. (1 aR, 2Z, 4E, 14R, 15aR) -8-chloro-9,1 1-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo [c] oxirene [2,3-k] [1 ] oxaciclotetradecin-6, 12 (7H, 14H) -dione Inhibitors of cancer metabolism - Many tumor cells have a metabolism markedly different from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose into pyruvate, increases and the pyruvate generated is reduced to lactate, instead of being oxidized further in the mitochondrial pathway of the tricarboxylic acid cycle (TCA). This effect is often seen even under aerobic conditions and is known as the Warburg effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a fundamental role in the metabolism of tumor cells, by reducing pyruvate in lactate, which can then be exported out of the cell . It has been shown that the expression of the enzyme is favored in many types of tumors. The alteration of glucose metabolism described in the Warburg effect is critical for the growth and proliferation of cancer cells and it has been shown that the inactivation of LDH-A using i-RNA leads to a reduction in cell proliferation and tumor growth in xenograft models.

D. A. Tennant et al., Nature Reviews, 2010, 267.

P. Leder, et al., Cancer Cell, 2006, 9, 425.

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. The pharmacological inhibition of FAS affects the expression of key oncogenes involved in the development and maintenance of cancer.

Alli er to /. Oncogene (2005) 24, 39-46. doi: 10.1038 Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with compounds of this invention.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration of a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent, such as one selected from the group consisting of anti-microtubule agents, coordination complexes with platinum, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, inhibitors of signal transduction pathways, inhibitors of angiogenesis that are tyrosine kinases not associated with receptors, immunotherapeutic agents, proapoptotic agents, inhibitors of cell cycle signaling; proteasome inhibitors; and inhibitors of cancer metabolism.

Compositions The pharmaceutically active compounds within the scope of this invention are useful as inhibitors of PERK in mammals, in particular humans, that need it.

Therefore, the present invention provides a method for treating cancer, arthritis and other conditions that require inhibition of PERK, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) also provide a method for treating the pathological states indicated above due to their demonstrated ability to act as inhibitors of PERK. The drug can be administered to a patient in need thereof by any conventional route of administration, including, but not limited to intravenous, intramuscular, oral, subcutaneous, intradermal and parenteral routes.

The pharmaceutically active compounds of the present invention are incorporated in convenient dosage forms such as capsules, tablets or injectable preparations. Solid or liquid pharmaceutical vehicles are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, alba earth, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. Likewise, the excipient or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as in the form of an ampoule, or an aqueous or non-aqueous liquid suspension.

The pharmaceutical compositions are obtained following conventional techniques of a pharmaceutical chemist involving mixing, granulation and compression, when necessary, for the tablet forms, or mixing, filling and dissolving the ingredients, when appropriate, to give the desired oral or parenteral products.

The dosage of the pharmaceutically active compounds of the present invention in a pharmaceutical dosage unit as described above will be an effective amount, preferably selected from the range of 0.001 to 100 mg / kg of active compound, preferably from 0.001 to 50 mg / kg. . When treating a human patient in need of a PERK inhibitor, the selected dose is preferably administered 1-6 times daily, orally or parenterally. Preferred forms of parenteral administration include topical, rectal, transdermal, injection and continuous infusion. Oral dosage units for human administration preferably contain 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages, is preferred. However, parenteral administration can also be used, at higher doses, when it is safe and convenient for the patient.

Optimal dosages to be administered can be readily determined by those skilled in the art, and will vary with the particular PERK inhibitor being used, the concentration of the preparation, the mode of administration and the progress of the disease state. Other factors that depend on the particular patient being treated will require adjusting the dosages, including the patient's age, weight, diet and time of administration.

The method of this invention for inducing PERK inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an PERK-inhibiting effective amount of a pharmaceutically active compound of the present invention.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a PERK inhibitor.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy.

The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer.

The invention also provides a pharmaceutical composition for use as a PERK inhibitor comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition for use in the treatment of cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with other active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a PERK inhibitor.

Without further preparation, it is believed that one skilled in the art, using the above description, can use the present invention to its fullest extent. Therefore, the following examples should be considered as merely illustrative and in no way limiting the scope of the present invention.

EXAMPLES Although particular embodiments of the present invention are described, those skilled in the art will appreciate that some changes and modifications can be made without departing from the spirit and scope of the invention.

The bicycloheteroaryl halides used in the invention as intermediate chemical products are listed below in the table. When available, the corresponding references of the synthetic preparation are given. For intermediate products without a cited literature reference, details of the synthetic preparation are included in the following examples.

EXAMPLE 1 1 - . 1 -methyl-3-? - (phenylacetyl) -2,3-dihydro-1 H-indol-5-in-1 H-pyrazolor3,4-dlpyrimidin-4-amine 5-bromo-1- (phenylacetyl) -2,3-dihydro-1 H-indole To a mixture of phenylacetic acid (0.687 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in?,? - dimethylformamide (DMF) (5 ml) was added Hunig's base (0.882 ml, 5, 05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-Bromo-2,3-dihydro-1 H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was poured into water, and the resulting precipitate was filtered and air dried to provide 5-bromo-1- (phenylacetyl) -2,3-dihydro-1 H-indole (1.24 g) as a brown solid. 1 - . 1-methi-3-f1- (phenylacetyl) -2, 3-dihydro-1 H-indol-5-Hl-1 H-pyrazolo [3,4-dlDirimidin-4-amine To 5-bromo-1- (phenylacetyl) -2,3-dihydro-1 H-indole (122 mg, 0.386 mmol), bis (pinacolato) diboro (125 mg, 0.491 mmol), adduct of PdCl2 (dppf) -CH2CI2 (28.6 mg, 0.035 mmol) were added 1,4-dioxane (2 ml) and ammonium acetate (81 mg, 1.052 mmol) in a 5 ml microwave vial. Then, gaseous N2 was bubbled into the mixture for 5 minutes, then capped and heated in an oil bath at 80 ° C. After 1 h, the reaction was cooled and then 3-bromo-1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (80 mg, 0.351 mmol), 2 M K 2 CO 3 (1 ml) and an additional 10 mg of PdC catalyst (dppf). Then, the vial was capped and heated in a microwave reactor for 5 minutes at 110 ° C. The reaction was then concentrated, then dissolved in 2 ml of DIVISO and the solid filtered off using a syringe filter and the filtrate was purified by HPLC: (HPLC conditions: Gilson System using the Trilution software with a Sunfire column 5u C18 (2) 100A.50X30.00 mm 5 micrometers, 7.3 minute experiment (47 ml / min, ACN / 20% H20, 0.1% TFA at 40% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was transferred to a 40 ml vial and lyophilized to isolate the trifluoroacetate salt of 1-methyl-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl. ] -1 H-pyrazolo [3,4-d] pyrimidin-4-amine (42 mg, 0.084 mmol, 24.02% yield) as a white solid. LC-MS (ES) m / z = 385 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.37 (1 H), 8.21 (d, J = 8.34 Hz, 1 H), 7.50 (s, 1 H), 7, 44 (dd, J = 1, 52, 8.34 Hz, 1 H), 7.24-7.38 (m, 5H), 4.24 (t, J = 8.59 Hz, 2H), 3, 97 (s, 3H), 3.90 (s, 2H), 3.24 (t, J = 8.34 Hz, 2H) the NH2 protons were not observed in the spectra.

EXAMPLE 2 3-. { 1-r (2,5-difluorophenynacetin-2,3-dihydro-1 H-indol-5-ylM-methyl-1 H-pyrazolof3.4-dlpyrimidin-4-amine 5-bromo-1 -1 (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indole To a mixture of (2,5-difluorophenyl) acetic acid (0.869 g, 5.05 mmol) and HATU (2.1 g, 5.55 mmol) in?,? - dimethylformamide (DMF) (10 ml) ) Hunig's base (0.882 mL, 5.05 mmol) was added, and the resulting mixture was stirred for 15 minutes at room temperature. 5-Bromo-2,3-dihydro-1 H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into water, and the resulting aqueous mixture was filtered to provide 5-bromo-1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indole (1.6 g) in the form of a brown solid. 3- (1 (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl.} - 1 -methyl-1 H -pyrazolo [3,4-dlpyrimidin-4-amine] To a mixture of 5-bromo-1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indole (160 mg, 0.454 mmol), bis (pinacolato) diboro (127 mg, 0.500 mmol ) and potassium acetate (134 mg, 1, 363 mmol) was added 1,4-dioxane (6 mL) and the mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (18.55 mg, 0.023 mmol) was added and the reaction mixture was stirred for 3 hours at 100 ° C in a sealed container. The reaction was cooled to room temperature. 3-Bromo-1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (104 mg, 0.454 mmol) and saturated aqueous solution of NaHCO 3 (2 mL) were added, and N 2 gas was bubbled through. through the mixture for 10 minutes. The adduct PdCl2 (dppf) -CH2Cl2 (18.55 mg, 0.023 mmol) was added, the vessel was sealed and the reaction mixture was stirred overnight at 100 ° C (LCMS: N13207-34suzu). The mixture was allowed to cool to room temperature and poured into water (-150 ml). The resulting mixture was filtered and the resulting solid was triturated with Et2Ü. To the solid in the filter was added a 90: 10 mixture of CHCl 3: CH 3 OH (-7 ml), and the resulting mixture was filtered. The filtrate was injected into columns of 90 g of S1O2. Flash chromatography on Si02 (gradient: from 100% CHCl3 to CHCl3: CH3OH: NH4OH 90: 10: 1) gave the title compound 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (160 mg) as a brown solid, 1 H NMR (400 MHz, DMSO-d 6) d 3.29 (t, J) = 8.34 Hz, 2 H), 3.94 (s, 3 H), 3.97 (s, 2 H), 4.30 (t, J = 8.46 Hz, 2 H), 7.14 - 7.31 (m, 3 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.53 (s, 1 H), 8.14 (d, J = 8.34 Hz , 1 H), 8.25 (s, 1 H) EXAMPLE 3 3-G1 - (phenylacetyh-2,3-dihydro-1 H-indol-5-yl-1 H-pyrazolor-3,4-d-pyrimidin-4-amine 3-n- (phenylacetyl) -2, 3-dihydro-1H-indol-5-ill-1H-Dirazolor3.4-dlDirimidin-4-amine To a mixture of 5-bromo-1- (phenylacetyl) -2,3-dihydro-1 H-indole (148 mg, 0.467 mmol), bis (pinacolato) diol (125 mg, 0.491 mmol) and potassium acetate (138 mg, 1, 402 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (19.08 mg, 0.023 mmol) was added and the reaction mixture was stirred for 3 hours at 100 ° C in a sealed container. The reaction was cooled to room temperature. 3-Bromo-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (100 mg, 0.467 mmol) and saturated aqueous solution of NaHCO 3 (2 mL) were added, and N 2 gas was bubbled through the mixture. for 10 minutes. The adduct PdCl2 (dppf) -CH2Cl2 (19.08 mg, 0.023 mmol) was added, the container was sealed, and the reaction mixture was stirred for 3 days at 100 ° C. The mixture was allowed to cool to room temperature and poured into water (-150 ml). The resulting mixture was filtered and the resulting solid was triturated with EtOAc. To the dark solid in the filter an 80:20 mixture of CHCl3: CH3OH (~7 mL) was added and the resulting mixture was filtered. The filtrate was injected into columns of 90 g of SiO2. Flash chromatography on SiO2 (gradient: from 100% CHCl3 to CHCl3: CH3OH: NH4OH 90: 10: 1) afforded the title compound. Trituration with Et20 yielded the title compound 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -1 H -pyrazolo [3,4-d] pyrimidin-4 -amine (35 mg) in the form of a gray solid. RN 1 H (400 MHz, DMSO-d6) d 3.24 (t, J = 8.34 Hz, 2 H), 3.89 (s, 2 H), 4.24 (t, J = 8.46 Hz) , 2 H), 7.22-7.40 (m, 6 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.50 (s, 1 H), 8.17 - 8.23 (m, 2 H), 13.51 (s, 1 H) EXAMPLE 4 7-methyl-5-ri- (phenylacetyl) -2,3-dihydro-1 H-indol-5-in-7H-pyrrolor-2,3-dlpyrimidin-4-amine 4-chloro-7-methyl-7H-pyrroloi2, 3-dlpyrimidine To 4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (15.2 g, 99 mmol) in?,? -dimethylformamide (DMF) (100 ml) at 0 ° C was added NaH at 60% (5.15 g, 129 mmol) in portions. After bubbling off H2, iodomethane (6.81 m, 109 mmol) was added dropwise, and then the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction mixture was poured slowly into water (~ 800 ml; Caution: evolution of H2 due to inactivation of excess NaH). The resulting solid was filtered and washed with water followed by hexanes to give 4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine (12.2 g) as an off-white solid. 5-bromo-4-chloro-7-methyl-7H-pyrrolof2, 3-dlpyrimidine To 4-chloro-7-methy1-7H-pyrrolo [2,3-d] pyrimidine (12.15 g, 72.5 mmol) in dichloromethane (DCM) (200 mL) was added NBS (13 , 55 g, 76 mmol) in portions, and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the solid was washed with water and dried to give 5-bromo-4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine (17 g) as an off-white solid . 5-bromo-7-methyl-7H-pyrrolo [2,3-d1-pyrimidin-4-amine A suspension of 5-bromo-4-chloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine (17 g , 69.0 mmol) in ammonium hydroxide (150 ml, 3852 mmol) was stirred for 2 days at 100 ° C in a sealed container. The reaction was allowed to cool to room temperature and filtered. The collected solid was washed with Et20 to give the product 5-bromo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (12.5 g) as a white solid. 7-methyl-5- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-γ-7H-pyrroloyl-2,3-dlpyrimidin-4-amine To a mixture of 5-bromo-1- (phenylacetyl) -2,3-dihydro-1 H-indole (139 mg, 0.440 mmol), bis (pinacolato) diboro (1.7 mg, 0.462 mmol) and potassium acetate (130 mg, 1, 321 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (19.08 mg, 0.023 mmol) was added and the reaction mixture was stirred for 3 hours. hours at 100 ° C in a hermetically sealed container. The reaction was cooled to room temperature. 5-Bromo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.440 mmol) and saturated aqueous solution of NaHCO3 (2 mL) were added and N2 gas was bubbled. through the mixture for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (17.98 mg, 0.022 mmol) was added, the vessel was sealed and the reaction mixture was stirred for 3 days at 100 ° C. The mixture was allowed to cool to room temperature and poured into water (~ 150 ml). The resulting mixture was filtered. The solid in the filter was mixed with an 80:20 mixture of CHCl3: CH3OH (~7 mL) and the resulting mixture was filtered. The filtrate was injected into columns of 90 g of SiO2. Flash chromatography on SiO2 (gradient: from 100% CHCl3 to CHCl3: CH3OH: NH4OH 90:10: 1) gave the product. Trituration with Et20 gave the title compound 7-methyl-5- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7H-pyrrolo [2,3-d] pyrimidine- 4-amine (22 mg) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6) d 3.21 (t, J = 8.21 Hz, 2 H), 3.73 (s, 3 H), 3.87 (s, 2 H), 4, 21 (t, J = 8.46 Hz, 2 H), 7.15-7.42 (m, 8 H), 8.11-8.15 (m, 2 H) EXAMPLE 5 3-Ri - (phenylacetyl) -2,3-dihydro-1 H-indol-5-intienof3l2-c1pyridin-4-amine In a sealed tube, 5-bromo-1- (phenylacetyl) -2,3-dihydro-1H-indole (0.658 g, 2.081 mmol), bispinacolatodiboro (0.634 g, 2.497 mmol) and potassium acetate (0.613 g) , 6.24 mmol) was added 1,4-dioxane (15 mL) and the mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred for 48 hours at 100 ° C. The mixture was cooled to room temperature and treated with 5 ml of water, 3-bromothieno [3,2-c] pyridin-4-amine (0.524 g, 2.289 mmol) and NaHCO3 (175 mg). The mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred overnight at 100 ° C. The mixture was poured into water and ethyl acetate, and then filtered. The filtrate was poured into a separating funnel. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO 4), filtered and concentrated. Flash chromatography on Si02 (gradient: 100% CHCl3 at CHCl3 / CH3OH / NH4OH 90: 10: 1) provided some fractions containing the desired product with impurities. The fractions were combined and evaporated. The resulting residue was dissolved in MeOH / ChbCb (1 ml / 5 ml). It was then dry-charged and purified on Analogix 25/14 silica, gradient EtOAc / hexane 0-100%. The compound came out with 95% EtOAc. The fractions with the pure compound were combined. The solvents were evaporated and the resulting residue was triturated in EtOAc to give as an off-white solid (280 mg) the title compound 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl. ] thieno [3,2-c] pyridin-4-amine. LC-MS (ES) m / z = 386.0 [M + H] +. H-NMR (400 MHz, DMSO-de) d ppm 8, 16 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 5.6 Hz, 1 H), 7.41 ( s, 1 H), 7.19-7.38 (m, 8 H), 5.41 (broad s, 2 H), 4.25 (t, J = 8.6 Hz, 2 H), 3, 89 (s, 2 H), 3.23 (t, 2 H).

EXAMPLE 6 3- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H -indole-5-yl) thienor3,2-c1pyridin-4-amine In a sealed tube, 5-bromo-1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indole (0.700 g, 1.988 mmol), bis (pinacolato) diborium (0.606 g, 2.385 mmol) and potassium acetate (0.585 g, 5.96 mmol) was added 1,4-dioxane (15 mL) and the mixture was degassed with N2. for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (0.081 g, 0.99 mmol) was added and the reaction mixture was sealed and stirred for 48 hours at 100 ° C. The mixture was cooled to room temperature and treated with 5 ml of water, 3-bromothieno [3,2-c] pyridin-4-amine (0.501 g, 2.186 mmol) and sodium bicarbonate (167 mg, 1.988 mmol). ). The mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred overnight at 100 ° C. The mixture was poured into water and ethyl acetate and then filtered. The filtrate was poured into a separating funnel. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. It was purified by Analogix 25/40 silica gel cartridge, eluting with a gradient of 0-100% EtOAc / hexane. The compound came out with 100% EtOAc in 10 minutes. The fractions with the pure compound were combined. The solvents were evaporated and dried to give the title compound 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine, in the form of an off-white solid (526 mg). LC-MS (ES) m / z = 422.2 [M + H] +. H-NMR (400 MHz, DMSO-d6) d ppm 8.11 (d, J = 8.3 Hz, 1 H), 7.82 (d, J = 5.6 Hz, 1 H), 7.42 ( s, 1 H), 7.35 (s, 1 H), 7, 12 - 7.31 (m, 5 H), 5.41 (broad s, 2 H), 4.31 (t, J = 8) , 3 Hz, 2 H), 3.96 (s, 2 H), 3.23-3.31 (m, 2 H).

EXAMPLE 7 3-r - (phenylacetyl) -213-dihydro-1 H-indol-5-yl-1- (3-pyridine-dinitrile-3,2-c-pyridine- 7- vodo-3-? - (phenylacetyl) -2, 3-dihydro-1 H -indole-5-ylthieno-3, 2-clpiridin-4-amine To a solution of 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine (150 mg, 0.389 mmol) in DMF (3.0 ml) cooled in an ice bath was added NIS (96 mg, 0.428 mmol). The reaction mixture was stirred at t.a. during one night. Water was poured into the mixture, the brown solid formed was filtered and dried to give 185 mg of the product 7- iodo-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] thieno [3,2-c] pyridin-4-amine. 3- 1- (phenylacetyl) -2.3-dihydro-1H-indol-5-ill ^ clpyridin-4-amine In a 25 ml pressure tube, 7-iodo-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin was loaded. 4-amine (182 mg, 0.356 mmol), 3-pyridinylboronic acid (43.7 mg, 0.356 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride complex (11) -dichloromethane (14, 53 mg, 0.018 mmol) and sodium carbonate (75 mg, 0.712 mmol) followed by dioxane (5 mL) and water (1 mL). The reaction was heated at 120 ° C for 30 min in a microwave reactor. Water (20 ml) and ethyl acetate (20 ml) were added and the layers were separated. The organic layer was washed with brine, concentrated and the residue was purified by silica gel chromatography (EtOAc in 0% -100% hexane) to give the title compound 3- [1- (phenylacetyl) -2.3 -dihydro-1 H-indol-5-yl] -7- (3-pyridinyl) thieno [3,2-c] pyridin-4-amine (85 mg) as a gray solid. LC-MS (ES) m / z = 463.1 [M + H] +. H-NMR (400 MHz, DMSO-ck) d ppm 8.88 (d, J = 1.8 Hz, 1 H), 8.62 (dd, J = 4.8, 1.5 Hz, 1 H), 8.18 (d, J = 8.1) Hz, 1 H), 8.10 (dt, J = 8, 1, 1, 9 Hz, 1 H), 7.96 (s, 1 H), 7.56 (dd, J = 8.1, 4 , 8 Hz, 1 H), 7.50 (s, 1 H), 7.23 - 7.40 (m, 7 H), 5.63 (broad s, 2 H), 4.26 (t, J = 8.5 Hz, 2 H), 3.90 (s, 2 H), 3.24 (t, 2 H) EXAMPLE 8 1 - . 1-methyl-4- (1-r (3-methylpheninacetill-2,3-dihydro-1 H-indol-5-? H -indazol-3-amine 5-Bromo-2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester To a stirred solution of 5-bromo-2,3-dihydro-1 H-indole (30 g, 151 mmol) and DMAP (0.4 g, 3.27 mmol, 0.02 equiv) in 150 ml of MeCN at room temperature was added B0C2O (43 g, 197 mmol, 1.3 eq) in one portion. The mixture was stirred at rt. After 10 min, the mixture gradually became a suspension. After 3 h, the suspension was filtered. The filter cake was washed with cold MeCN (60 ml), and suction filtered with a laboratory vacuum system for 5 h to give the 5-bromo-2,3-dihydro-1 H-indole-1-carboxylate. 1, 1-dimethylethyl ether (approximately 28.5 g before drying). LCMS (ES) m / z = 244, 242 as highlighted fragments. 1 H NMR (400 MHz, DMSO-de) d ppm 1.50 (s, 9 H), 3.06 (t, J = 8.7 Hz, 2 H), 3.91 (t, J = 8.7 Hz, 2 H), 7.31 (dd, J = 8.5, 1, 9 Hz, 1 H), 7.38 (s, 1 H), 7.51 - 7.71 (broad s, 0, 6 H). 5- (4,4.5.5-tetramethyl-1,3.2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl A mixture of 1,1-dimethylethyl 5-bromo-2,3-dihydro-1 H-indole-1-carboxylate (32 g, 107 mmol, 1 equiv), bis (pinacolato) diboro (32.7 g, 129 mmol, 1.2 equiv), adduct of PdCI2 (dppf) -CH2Cl2 (4.38 g, 15.37 mmol, 0.05 equiv) and potassium acetate (26.3 g, 268 mmol, 2.5 equiv) in 350 ml of dioxane in a 1 liter flask was evacuated and flushed with nitrogen, which was repeated 5 times. The mixture was heated at 100 ° C for 18 h. The LCMS analysis showed the complete conversion. The mixture was filtered through Celite and washed with EtOAc (500 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (700 mL) and brine (300 mL). The organic layer was extracted with EtOAc (200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DCM and divided into 7 equal parts. Each was absorbed in a dry charge cartridge just before chromatography.

Purification was done in 120 g silica gel cartridges using gradient elution of EtOAc in 1% hexane to EtOAc in 40% hexane. The desired product eluted in EtOAc in 17-24% hexane. The combined fractions were concentrated in vacuo to give a waxy cake in the recovery flask, which was disintegrated and dried under vacuum at t a. for 20 h to give the product (30.54 g, 82% yield) as a light yellow waxy solid. LC-MS (ES) m / z = 346 [M + H] +, fragment highlighted at 290 [M-55] +. 1 H NMR (400 MHz, D SO-d 6) d ppm 1.27 (s, 12 H), 1.50 (s, 9 H), 3.05 (t, J = 8.6 Hz, 2 H), 3.91 (t, J = 8.7 Hz, 2 H), 7.43-7.52 (m, 2 H), 7.58-7.80 (broad s, 1 H). 5- (2-cyano-3-fluorophenyl) -2,3-dihydro-H-indol-1-carboxylate 1,1-dimethylethyl A mixture of 2-fluoro-6-iodobenzonitrile (2.65 g, 10.73 mmol), 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1-carboxylate of 1,1-dimethylethyl (3.78 g, 10.95 mmol, 1.02 equiv), tricyclohexylphosphine (301 mg, 1.07 mmol, 0.1 equiv), Pd2 (dba) 3 (491 mg, 0.54 mmol, 0.05 equiv) and K3P04 (3.87 g, 18.24 mmol, 1.7 equiv) in 40 ml of dioxane and 10 ml of water in a 150 ml pressure vessel was bubbled under an argon atmosphere for 10 min. The mixture was capped and heated in an oil bath at 100 ° C for 18 h. The LCMS analysis showed the complete conversion. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (130 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The dark brownish oil was stored in a refrigerator for 20 h, and turned into a cake. The trituration in DCM / hexane (1: 4), disintegration of the cakefiltration and vacuum drying at room temperature gave the 5- (2-cyano-3-fluorophenyl) -2,3-dihydro-1 H-indole-1-carboxylate of 1,1-dimethylethyl (2.63 g) in shape of a gray solid. The filtrate was concentrated in vacuo and absorbed on a dry-loaded cartridge. Purification was done on RS-120 g silica gel cartridge using gradient elution of EtOAc in 1% hexane to EtOAc in 40% hexane. The product eluted in EtOAc in 29-34% hexane. Concentration in vacuo and further vacuum drying gave 5- (2-cyano-3-fluorophenyl) -2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (0.77 g) in shape of a yellow foam. 5- (3-amino-1-methyl-1 H-indazol-4-in-2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl) To a suspension of 1,1-dimethylethyl 5- (2-cyano-3-fluorophenyl) -2,3-dihydro-1 H-indole-1-carboxylate (1.60 g, 4.73 mmol) in 30 ml of EtOH were added 7 ml of methylhydrazine in one portion. The mixture was heated in an oil bath at 100 ° C for 24 h. The LCMS analysis showed the complete conversion. The mixture was cooled and concentrated in vacuo. The residue was partitioned between DCM (60 ml) and water (30 ml). The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to give 5- (3-amino-1-methyl-1 H-indazol-4-yl) -2,3-dihydro-1 H-indole. 1, 1-dimethylethyl 1-carboxylate in the form of a creamy foamy solid (1.70 g). 4- (2,3-dihydro-1 H-indol-5-in-1-methyl-1 H -indazol-3-amine To a stirred suspension of 5- (3-amino-1-methyl-1 H 1,4-indole-4-yl) -2,3-dihydro-1 H-indole-1-carboxylate (1.70 g, 4.66 mmol) in 20 ml of EtOH was added with 12 ml of HCl. 2 N The mixture was heated at 75 ° C for 90 hrs LCMS analysis showed complete conversion The mixture was cooled and concentrated in vacuo The oily residue was diluted with 40 ml of water and the pH was adjusted to ~ 10 by addition of 1 N NaOH (pH paper) The milky mixture was extracted with MeOH in 10% DCM (100 ml, then 2 x 25 ml) The organic layers were dried over Na 2 SO 4, filtered and concentrated in vacuo. to give 4- (2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H-indazol-3-amino as a brownish foaming solid (1.13 g). LC-MS (ES) m / z = 265 [M + Hf. 1-methyl-4-. { 1 -i (3-methylphenyl) acetyl-2,3-dihydro-1 H-indol-5-yl) -1 H -indazol-3-amine To a clear solution of 4- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H-indazol-3-amine (200 mg, 0.76 mmol, 1 equlv) , (3-methylphenyl) acetic acid (14mg, 0.76 mmol, 1 equiv) and DIEA (145 ul, 0.83 mmol, 1.1 equiv) in 4 ml of DCM was added in a solid HATU portion (316 mg, 0.83 mmol, 1.1 equiv). The mixture was stirred at t.a. for 20 h. The LCMS analysis showed the complete conversion. The suspension was filtered. The filtrate was adsorbed in a dry loading cartridge. The purification was done in a silica gel cartridge SF25-24 g using gradient elution of EtOAc in 1% hexane to 100% EtOAc. The product eluted in 100% EtOAc as a broad but well-defined peak. Concentration in vacuo gave a white foam (320 mg). The LCMS analysis showed that the purity was only 84% with 1 1% of a major impurity. This material was dissolved in EtOAc (75 mL) and washed with water (25 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The LCMS analysis showed that there were still impurities present. The material was dissolved in EtOAc (100 mL) while still remaining some material stuck to the wall of the 100 mL recovery flask, to which 3 mL of MTBE was added. The mixture initially became turbid and was immersed in a water bath at (40 ° C). The turbidity disappeared and then solids began to form on the walls. A spatula was used to scrape the flask. The mixture was then cooled to room temperature and the suspension was filtered. The solids (light brown) were washed with MTBE (2 ml). Analysis of both LCMS and NMR showed that this lot was quite pure. The solid was dried under vacuum at 65 ° C for 16 h to give 210 mg as a brown solid. LCMS (ES) m / z = 397 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.31 (s, 3 H), 3.23 (t, J = 8.3 Hz, 2 H), 3.78 (s, 3 H), 3 , 83 (s, 2 H), 4.23 (t, J = 8.6 Hz, 2 H), 4.38 (s, 2 H), 6.78 (d, J = 5.8 Hz, 1 H), 7.05-7.15 (m, 13 H), 7.20-7.26 (m, 2 H), 7.28-7.38 (m, 3 H), 8.16 (d , J = 8.3 Hz, 1 H).

EXAMPLE 9 3-ri- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yn-7- (4-pyridinyl) thienor-3, 3-clpyridin-4-amine A mixture of 7-iodo-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine (101 mg, 0.198 mmol ), pyridine-4-boronic acid, pinacol ester (53 mg, 0.258 mmol) and adduct of PdCl2 (dppf) -CH2Cl2 (8 mg, 9.80 pmol) in 1,4-dioxane (1.5 mi) and Saturated aqueous sodium bicarbonate solution (0.6 ml, 0.600 mmol) was degassed with nitrogen for 10 minutes in a microwave vial. Then, the vial was capped and the mixture was stirred at 120 ° C in the microwave for 30 min. The LCMS analysis showed the Complete conversion into the desired product, together with a small de-ionized by-product. The mixture was cooled, poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The extracts were washed with brine (1 * 15 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g of S1O2, gradient of EtOAc in hexanes at 25% -100% over 30 minutes, then EtOAc for 10 minutes, then MeOH in 0-10% EtOAc at room temperature. 20 minutes) to give 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (4-pyridinyl) thieno [3,2-c] pyridin-4 -amine (66 mg, 0.136 mmol, 68.6% yield) as a beige solid. LC / MS (ES) m / z = 463 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d 3.24 (t, J = 8.46 Hz, 2 H), 3.90 (s, 2 H), 4.26 (t, J = 8.46 Hz) , 2 H), 5.74 (broad s, 2 H), 7.23-7.39 (m, 7 H), 7.52 (s, 1 H), 7.70-7.75 (m, 2 H), 8.09 (s, 1 H), 8.18 (d, J = 8.34 Hz, 0 H), 8.65- 8.72 (m, 2 H).

EXAMPLE 10 3- < 1-G (2.5? Difluorophenol) acetin-2,3-dihydro-1 H-indol-5-yl) -7- (3-pyridinyl) thienor-3-c-pyridin-4-amine 3- (1-f (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl) -7-yodotienoí3,2-clpiridin-4-amine To a solution of 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl} thieno [3,2-c] pyridin-4-amine (150 mg, 0.389 mmol) in DMF (6.0 mL) cooled in an ice bath was added NIS (264 mg, 1.174 mmol). The reaction mixture was stirred at room temperature overnight. Water was poured into the mixture, the brown solid formed was filtered and dried to give the product 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodothieno [3,2-c] pyridin-4-amine as a brown solid (581 mg). LCMS (ES) m / z = 548.2 [M + H] +. 3- (1 - [(2,5-difluorophenyl) acetyl-2,3-dihydro-1 H -indol-5-yl) -7- (3-pyridinyl) thienof3,2-c1pyridin-4-amine In a microwave reaction tube of 25 ml, the 3- was loaded. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodothieno [3,2-c] pyridin-4-amine (150 mg, 0.274 mmol), 3-pyridinylboronic acid (33.7 mg, 0.274 mmol), 1,1'-bis (d) dichloride complex Phenylphosphino) ferrocene palladium (II) -dichloromethane (1119 mg, 0.014 mmol) and sodium carbonate (58.1 mg, 0.548 mmol) followed by dioxane (50 mL) and water (100 mL). The reaction was heated at 120 ° C for 30 min in a microwave reactor. Ethyl acetate (20 ml) was added and the layers separated. The organic layer was washed with brine, concentrated and the residue was purified by chromatography on silica gel (EtOAc in 0% -100% hexanes). The product came out in 100% EtOAc, the fractions with the product were combined, evaporated to dryness to give the title compound as a light gray solid (112 mg). 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.88 (d, J = 2.0 Hz, 1 H), 8.62 (dd, J = 4.8, 1, 3 Hz, 1 H), 8.04 - 8.18 (m, 2 H), 7.97 (s, 1 H), 7.56 (dd, J = 7.6, 4.8 Hz, 1 H), 7.51 (s) , 1 H), 7.39 (s, 1 H), 7.14 - 7.32 (m, 4 H), 5.64 (broad s, 2 H), 4.32 (t, J = 8, 3 Hz, 2 H), 3.97 (s, 2 H), 3.29 (t, 2 H).

EXAMPLE 11 3-J 1 -r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H -indol-5-yl) -7- (1 H -pyrazol-3-yl) thienor 3,2-c 1pyridin-4-amine In a 25 ml microwave reactor vial, the 3- was loaded. { 1- [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodothieno [3,2-c] pyridin-4-amine (150 mg, 0.274 mmol), 1 H-pyrazol-3-ylboronic acid (30.7 mg, 0.274 mmol), dichloride complex of 1.1 '-bis (diphenylphosphino) ferrocene-palladium (II) -dichloromethane (1.19 mg, 0.014 mmol) and sodium carbonate (58.1 mg, 0.548 mmol) followed by dioxane (5 ml) and water (1 ml) . The reaction was heated at 120 ° C for 30 min in a microwave reactor. Ethyl acetate (20 ml) was added and the layers separated. The organic layer was washed with Brine, concentrated and the residue was purified by chromatography on silica gel (EtOAc in 0% -100% hexanes). The product was left in 100% EtOAc in 5 minutes, the fractions with the product were combined and evaporated to dryness to give the title compound as a light gray solid (48 mg). LC / MS (ES) m / z = 488.2 [M + Hf. 1 H NMR (400 MHz, DMSO-de) d ppm 12.99 (s, 1 H), 8.36 (s, 1 H), 8, 12 (d, J = 8, 1 Hz, 1 H), 7.85 (s, 1 H), 7.48 (s, 1 H), 7.38 (s, 1 H), 7, 14 - 7.31 (m, 4 H), 6.84 (s, 1 H), 5.50 (broad s, 2 H), 4.32 (t, J = 8.5 Hz, 2 H), 3.96 (s, 2 H), 3.25 - 3.32 (s). m, 2 H).

EXAMPLE 12 4- (1-r (2,5-difluoropheninacetin-2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H-indazol-3-amine To a clear solution of 4- (2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H-indazol-3-amine (300 mg, 1.14 mmol, 1 equiv), acid (2,5-difluoro) phenylacetic (195 mg, 1.14 mmol, 1 equiv) and DIEA (218 ul, 1.25 mmol, 1.1 equiv) in 4 ml of DCM was added at room temperature in a portion HATU solid (475 mg, 1.25 mmol, 1.1 equiv). The mixture was stirred at room temperature for 20 h. The LCMS analysis showed the conversion complete The suspension was filtered, and the solid was washed with water (2x3 mL) and with MTBE (2x2 mL), then dried over P205 under vacuum for 20 h to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 with one drop of TFA) d ppm 3.30 (t, J = 8.2 Hz, 2 H), 3.96 (s, 2 H), 4.04 (s, 3 H), 4.31 (t, J = 8.5 Hz, 2 H), 7.10 - 7.27 (m, 4 H), 7.31 (d, J = 8.3 Hz, 1 H ), 7.43 (s, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.66 (d, J = 8.6 Hz, 1 H), 8, 14 ( d, J = 8.3 Hz, 1 H).

EXAMPLE 13 3-G1 - (phenylacetyl) -2,3-dhydro-1 H-indol-5-n-7- (1 H -pyrazol-4-yl) thienor 3,2-clpyridin-4-amine A mixture of 7-iodo-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine (101 mg, 0.198 mmol ), 1-Boc-pyrazole-4-boronic acid pinacol ester (88 mg, 0.299 mmol) and PdCI2 (dppf) -CH2Cl2 adduct (9 mg, 0.011 mmol) in 1,4-dioxane (2.0 ml) ) and saturated aqueous sodium bicarbonate solution (0.6 ml, 0.600 mmol) was degassed with nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120 ° C in the microwave for 30 min. The LCMS analysis showed the complete conversion in the des-Boc product. The mixture cooled, poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The extracts were washed with brine (1 * 15 ml), dried (IS ^ SC), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g of Si02, EtOAc gradient in 50% -100% hexanes over 15 minutes, then EtOAc for 5 minutes, then MeOH in 0-10% EtOAc at 20 minutes) to give 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (1 H -pyrazol-4-yl) thieno [3.2 -c] pyridin-4-amine (50 mg, 0.105 mmol, 53.3% yield) as a light gray solid. LC / MS (ES) m / z = 452 [+ H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.24 (t, J = 8.34 Hz, 2 H), 3.89 (s, 2 H), 4.26 (t, J = 8.46 Hz) , 2 H), 5.40 (broad s, 2 H), 7.22-7.30 (m, 2 H), 7.30-7.40 (m, 5 H), 7.48 (s, 1 H), 7.95 (broad s, 1 H), 8.06 (s, 1 H), 8, 12 - 8.21 (m, 2 H), 13, 10 (broad s, 1 H).

EXAMPLE 14 7- (1-methyl-1 H -pyrazol-4-yl) -3-n-phenylacetyl) -2,3-dihydro-1 H-indol-5-nthieno [3T2-c1pyridin-4-amine] A mixture of 7-iodo-3- [1 - (phenylacetyl) -2,3-dihydro-H-indol-5- [3,2-c] pyridin-4-amine (102 mg, 0.199 mmol), acid pinacol ester 1-methylprazole-4-boronic acid (60 mg, 0.288 mmol), and adduct of PdC ^ ídppf) -CH2Cl2 (8 mg, 9.80 μ? T) in 1,4-dioxane (2 , 0 ml) and saturated aqueous sodium bicarbonate solution (0.6 ml, 0.600 mmol) was degassed with nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120 ° C in the microwave for 30 min. The LCMS analysis showed the complete conversion. The mixture was cooled, poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The extracts were washed with brine (1 * 15 ml), dried (a2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g of S02, EtOAc gradient in 50% -100% hexanes over 10 minutes, then EtOAc for 5 minutes, then MeOH in 0-10% EtOAc. over 20 minutes) to give 7- (1-methyl-1 H -pyrazol-4-yl) -3- [1 - (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl. ] thieno [3,2-c] pyridin-4-amine (69 mg, 0.141 mmol, 70.6% yield) as a light gray solid. LC / MS (ES) m / z = 466 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.24 (t, J = 8.46 Hz, 2 H), 3.89 (s, 2 H), 3.93 (s, 3 H), 4, 26 (t, J = 8.46 Hz, 2 H), 5.41 (broad s, 2 H), 7.22-7.30 (m, 2 H), 7.30-7.39 (m, 5 H), 7.49 (s, 1 H), 7.88 (s, 1 H), 8.03 (s, 1 H), 8.14 (s, 1 H), 8.17 (d, J = 8.08 Hz, 1 H).

EXAMPLE 15 3- (1-r (2-fluorophenyl) acet'n-2,3-dihydro-1 H-indol-5-yl> -1-methyl-1 H-pyrazolof3,4-dlpyrimidin-4-amine 5- (4-amino-1-methyl-1 H -pyrazolo [3,4-dlpyrimidin-3-yl] -2,3-dhydro-1 H -indole-1-carboxylate of 1, 1- dimethylethyl Into a 25 ml pressure tube, 3-bromo-1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (670 mg, 2.94 mmol), 5- (4, 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (1014 mg, 2.94 mmol) , 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) -dichloromethane dichloride complex (120 mg, 0.147 mmol) and sodium carbonate (494 mg, 5.88 mmol) followed by dioxane (8 ml) and water (2 mi). The reaction was heated at 120 ° C for 40 minutes in a microwave reactor. The LCMS analysis showed no more starting product. The reaction was cooled to room temperature, the mixture was transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and greasy black solid remaining in the tube (50 ml of EtOAc was added in total to the mixture). ). A white solid formed in the brown solution. The solid was filtered to give the title product (764 mg). 3- (2,3-dihydro-1 H-indol-5-n-1-methyl-1 H-pyrazoloyl-3,4-dlpyrimidin-4-amine-2HCl In a 250 ml round bottom flask, 5- (4-amino-1-methyl-H-pyrazolo [3,4-d] pyrimidin-3-yl) -2,3-dihydro-H-indole was added. 1, 1-dimethylethyl 1-carboxylate (745 mg, 2.033 mmol) followed by 4 M HCl in dioxane (12.2 ml). The mixture was stirred at room temperature overnight. The LCMS analysis showed no more starting material. The light brown solid in the reaction mixture was filtered, washed with 20 ml of EtOAc, and dried to give the desired product as an off-white solid. LC / MS (ES) m / z = 267, 1 [M + H] + 3-. { 1-r (2-fluorophenyl) acetyl-2,3-dihydro-H-indol-5-yl) -1-methyl-1 H-pyrazolo [3,4-d1-pyrimidin-4-amine] In a 20 ml vial, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-amine -2HCl (70 mg, 0.206 mmol), (2-fluorophenyl) acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The white solid was filtered to give the product. LC / MS (ES) m / z = 403.2 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.25-3.32 (m, 2 H), 3.91-3.99 (m, 5 H), 4.31 (t, J = 8, 46 Hz, 2 H), 7, 16 -7.24 (m, 2 H), 7.32-7.39 (m, 2 H), 7.44 (d, J = 8.08 Hz, 1 H ), 7.53 (s, 1 H), 8.15 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 16 3- (1-r (3-fluorophenyl) acetin-2,3-dihydro-1 H -indol-5-ylH-methyl-1 H-pyrazolor-3,4-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine-2HCl (70 mg, 0.206 mmol), (3-fluorophenyl) acetic acid (31.8 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base ( 144 mL, 0.825 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The white solid was filtered to give the product. LC / MS (ES) m / z = 403.2 [M + H] +. 1 H NMR (400 MHz, DMSO-d6) d ppm 3.26 (t, J = 8.46 Hz, 2 H), 3 , 93 (s, 5 H), 4.25 (t, J = 8.46 Hz, 2 H), 7.11 (s, 1 H), 7.13 - 7, 17 (m, 2 H), 7.39 (d, J = 6.82 Hz, 1 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.51 (s, 1 H), 8.18 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 17 1 - . 1 -methyl-3-? -r (2-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-ylM H-pyrazolor 3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine-2HCl (70 mg, 0.206 mmol), acid (2-methylphenyl) acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (144 mL, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The white solid was filtered and dried to give the product. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.25 (s, 3 H), 3.23-3.31 (m, 2 H), 3.90 (s, 2 H), 3.94 ( s, 3 H), 4.28 (t, J = 8.59 Hz, 2 H), 7.15 - 7.22 (m, 4 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.52 (s, 1 H), 8.18 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 18 1-methyl-3- (1-r (3-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolor 3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine-2HCl (70 mg, 0.206 mmol), (3-methylphenyl) acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144). mi, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The white solid was filtered to give the product. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.30 (s, 3 H), 3.24 (d, J = 8.34 Hz, 2 H), 3.84 (s, 2 H), 3 , 93 (s, 3 H), 4.19 - 4.27 (m, 2 H), 7.07 - 7.14 (m, 3 H), 7.23 (t, J = 7.58 Hz, 1 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.50 (s, 1 H), 8.20 (d, J = 8.34 Hz, 1 H), 8, 24 (s, 1 H).

EXAMPLE 19 3-G1 - (phenylacetyl-2,3-dihydro-1 H-indol-5-in-7- (1, 2,3,6-tetrahydro-4-pyridinyl) thienof3.2-clpyridin-4-amine 4- (4-amino-3-M- (phenylacetyl) -2,3-dihydro-1 H -indole-5-intienor3,2-clpyridin-7-yl) -3,6-dihydro-1 (2H) - 1,1-dimethylethyl pyridinecarboxylate A mixture of 7-iodo-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] thieno [3,2-c] pyridin-4- amine (298 mg, 0.583 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (238 mg, 0.770 mmol), and PdCl2 adduct (dppf) -CH2Cl2 (24 mg, 0.029 mmol) in, 4-dioxane (6 mL) and saturated aqueous sodium bicarbonate solution (2 mL, 2.000 mmol) was degassed with nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120 ° C in the microwave reactor for 30 min. The LCMS analysis showed the complete conversion to the product. The mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The extracts were washed with brine (1 * 75 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g of S1O2, gradient of EtOAc in hexanes at 25% -100% over 45 minutes, then EtOAc for 5 minutes). minutes) to give the 4-. { 4-amino-3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] t-ene [3,2-c] pyridin-7-yl} 1,3-dihydro-1 (2H) -pyridinecarboxylate 1,1-dimethylethyl ester (280 mg, 0.494 mmol, 85% yield) as a beige solid. LC / MS (ES) m / z = 567 [M + H] +. 3-M - (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl-1- (1, 2,3,6-tetrahydro-4-pyridinyl) thieno [3,2-c1pyridin- 4-amine A mixture of 4-. { 4-amino-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-7-yl} 1,3-dihydro-1 (2H) -pyridinecarboxylic acid 1,1-dimethylethyl ester (54 mg, 0.095 mmol) and TFA (1.0 mL, 12.98 mmol) in dichloromethane (DCM) (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. After the mixture was concentrated in vacuo, NaHCO 3 (5 mL) was added and extracted with methylene chloride (3 x 5 mL). The extracts were dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 12 g of S1O2, gradient from DCM to DCM / MeOH / NH4OH 90/10/1 over 20 minutes) to give 3- [1- (phenylacetyl) -2, 3-dihydro-1 H-indol-5-yl] -7- (1, 2,3,6-tetrahydro-4-pyridinyl) thieno c] pyridin-4-amine (33 mg, 0.064 mmol, 66.8% of performance) in the form of a beige solid. LC / MS (ES) m / z = 467 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) δ 2.42 (d, J = 1.77 Hz, 2 H), 2.96 (t, J = 5.56 Hz, 2 H), 3.23 (t , J = 8.34 Hz, 2 H), 3.43 (d, J = 3.03 Hz, 2 H), 3.89 (s, 2 H), 4.25 (t, J = 8.46 Hz, 2 H), 5.40 (broad s, 2 H), 6.16 (broad s, 1 H), 7.19 - 7.39 (m, 7 H), 7.43 (s, 1 H ), 7.79 (s, 1 H), 8, 16 (d, J = 8.34 Hz, 1 H).

EXAMPLE 20 3- (1- (r3- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1H-indol-5-yl) thien c | pyridin-4-amine 5- (4-aminothienor3,2-c1pyridin-3-yl) -2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl Into a 250 ml round bottom flask were added 3-bromothieno [3,2-c] pyridin-4-amine (2, 65 g, 11.59 mmol), 5- (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1 - 1,1-dimethylethyl carboxylate (5 g, 14.48 mmol), 1,4-dioxane (50 ml) and 2 M potassium carbonate (21.72 ml, 43.4 mmol). The reaction was capped and swept with N2 and then adduct of PdCl2 (dppf) -CH2Cl2 (0.591 g, 0.724 mmol) was added. The reaction was then refluxed overnight under an inert atmosphere. The reaction mixture was cooled to room temperature and then filtered through a plug of silica. It was then diluted with 150 ml of H20 and extracted with ethyl acetate (3 × 150 ml). The organic extracts were combined and dried over Na 2 SO 4 and then concentrated to a black residue. Then, this was purified by normal phase chromatography (50-100% EtOAc / hexanes). The fractions with product were combined and were concentrated to give the 5- (4-aminothieno [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indol-1-carboxylate 1,1-dimethylethyl ester (5.19 g , 13.42 mmol, 93% yield) as an off-white solid. LC / MS (ES) m / z = 368.2 [M + Hf 3- (2,3-dihydro-1 H-indol-5-yl) thienor3.2-clpyridin-4-amine 5- (4-aminothieno [3,2-c] pyridin-3-yl) -2, 3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (5.19 g, 14.12 mmol) was taken up in 4 M HCl in dioxane (100 mL, 400 mmol) as a suspension and left Stir at room temperature overnight. The reaction was then filtered and washed with dioxane to give 3- (2,3-dihydro-H-indol-5-yl) thieno [3,2-c] pyridin-4-amine (3.44 g) in form of a whitish solid. LC / MS (ES) m / z = 268, 1 [M + H] + 3- (1- (r3- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c1pyridin-4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-trifluoromethylphenylacetic acid (76 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N, N-dimethylformamide (DMF) (2 ml) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3- (1 - { [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H -indol-5-yl) thieno [3, 2-c] pyridin-4-amino (106.1 mg) as an orange solid. LC / MS (ES) m / z = 454.2 [M + H] +. MN 1 H (400 MHz, DMSO-d 6) d ppm 8.15 (d, J = 8.3 Hz, 1 H), 7.84 (d, = 6.1 Hz, 1 H), 7.69 (s) , 1 H), 7.57-7.67 (m, 3 H), 7.52 (s, 1 H), 7.36 (d, J = 5.8 Hz, 2 H), 7.25 ( d, J = 8.1 Hz, 1 H), 5.79 (broad s, 2 H), 4.30 (t, J = 8.5 Hz, 2 H), 4.05 (s, 2 H) 3.27 (t, 2 H).

EXAMPLE 21 3- (1-r (2-chlorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl> thienor3,2-c1pyridin-4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). The?,? - dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 ml) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine (85.3 mg) as a pink solid. LC / MS (ES) m / z = 420.2 [M + H1 + 1 H NMR (400 MHz, DMSO-d6) 8 ppm 3.28 (t, J = 8.34 Hz, 2 H), 4.02 ( s, 2 H), 4.32 (t, J = 8.46 Hz, 2 H), 5.43 (broad s, 2 H), 7.23 (d, J = 8.08 Hz, 1 H) , 7.26 (d, J = 5.56 Hz, 1 H), 7.31-7.37 (m, 3 H), 7.39-7.44 (m, 2 H), 7.45- 7.51 (m, 1 H), 7.83 (d, J = 5.56 Hz, 1 H), 8, 11 (d, J = 8.08 Hz, 1 H).

EXAMPLE 22 3- (1-r (3-chlorophenyl) acetyl-2-dihydro-1 H-indol-5-yl-N-3-chloropyridin-4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). Added?,? - dimethylformamide (DMF) (2 ml) and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine (42.3 mg) as a yellow solid. LC / MS (ES) m / z = 420.2 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.25 (s, 2 H), 3.93 (s, 2 H), 4.26 (s, 2 H), 5.41 (broad s, 2 H), 7.20-7.30 (m, 3 H), 7.32-7.36 (m, 2 H), 7.37-7.40 (m, 2 H), 7.42 (s) , 1 H), 7.82 (d, J = 5.56 Hz, 1 H), 8.14 (d, J = 8.08 Hz, 1 H).

EXAMPLE 23 3- (1- (r3- (methyloxy) phenynacetyl V2.3-dihydro-1 H-indol-5-yl) thienor3.2-clpirid 4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 ml, 1.496 mmol). The?,? - dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3- (1 - { [3- (methyloxy) phenyl] acetyl} -2,3-dhydro-1 H -indol-5-yl) thieno [ 3,2-c] pyridin-4-amine (69.4 mg) as a white solid. LC / MS (ES) m / z = 416.2 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.22 (t, J = 8.34 Hz, 2 H), 3.75 (s, 3 H), 3.86 (s, 2 H), 4 , 23 (t, J = 8.46 Hz, 2 H), 5.54 (broad s, 2 H), 6.84 (dd, J = 8.21, 2.40 Hz, 1 H), 6, 87-6.91 (m, 2 H), 7.21-7.27 (m, 2 H), 7.29 (d, J = 5.56 Hz, 1 H), 7.33 (s, 1 H), 7.44 (s, 1 H), 7.83 (d, J = 5.81 Hz, 1 H), 8.17 (d, J = 8.34 Hz, 1 H).

EXAMPLE 24 3- (1- (r2- (methyloxy) phenyl-1-acetyl) -2,3-dihydro-1 H-indol-5-yl) thienor3,2-clpyridin- Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-methoxyphenylacetic acid (62.2 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N, N-dimethylformamide (DMF) (2 ml) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 ml) and extracted with EtOAc (5 ml). The organic extracts were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) thieno [3, 2-c] pyridin-4-amine (40.6 mg) as a white solid. LC / MS (ES) m / z = 416.2 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 3.25 (t, 2 H), 3.74 - 3.84 (m, 5 H), 4.27 (t, 2 H), 6.01 ( s wide, 2 H), 6.93 (t, 1 H), 7.01 (d, J = 7.83 Hz, 1 H), 7.20 (dd, J = 7.33, 1, 52 Hz , 1 H), 7.22-7.31 (m, 2 H), 7.36 (s, 1 H), 7.42 (d, J = 6.06 Hz, 1 H), 7.57 ( s, 1 H), 7.84 (d, J = 6.06 Hz, 1 H), 8.14 (d, J = 8.08 Hz, 1 H).

EXAMPLE 25 3-ri- (2-naphthalenylacetyl) -2,3-dihydro-1 H-m ^ amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1H-indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed of HATU (142 mg, 0.374 mmol), 2-naphthylacetic acid (69.6 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). The?,? - dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3- [1- (2-naphthalenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine ( 70 mg). LC / MS (ES) m / z = 436.2 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.19 - 3.29 (m, 2 H), 4.07 (s, 2 H), 4.31 (t, J = 8.46 Hz, 2 H), 5.45 (broad s, 2 H), 7.20 - 7.29 (m, 2 H), 7.33 (s, 1 H), 7.42 (s, 1 H), 7, 46-7.55 (m, 3 H), 7.80-7.85 (m, 2 H), 7.86-7.95 (m, 3 H), 8.18 (d, J = 8, 08 Hz, 1 H).

EXAMPLE 26 3-ri- (phenylacetyl) -2,3-dihydro-1 H-indol-5-n-7- (4-piperidininthienor3.2- c1pyridin-4-amine 4- (4-amino-3-ri- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl-1-thienor-3, 2-clpyridin-7-yl}. -1-p-peridincarboxylate of 1 , 1-dimethylethyl A suspension of 4-. { 4-amino-3- [1- (phenylacetyl) -2, 3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-7-yl} 3,3-dihydro-1 (2H) -pyridinecarboxylate, 1- (dimethylethyl) (220 mg, 0.388 mmol) and Pd / C, 10% by weight (dry basis), wet, Degussa type E101 NE / W approximately 50% water (25 mg, 0.012 mmol) in ethanol (10 mL) was stirred under a hydrogen atmosphere for 2 hours. The starting material did not appear to dissolve at any time (the mixture was a thick gray suspension), so tetrahydrofuran (THF) (15 ml) was added. It was stirred under a druing hydrogen atmosphere for another 17 h, and then filtered. The LCMS analysis seemed to indicate that there was little or no conversion (based on peak mass). The filtrate was subjected to hydrogenation with 10% Pd / C in a H-Cube® reactor at 40 ° C and 40 bar for 23 hours (the actual reaction time was shorter due to an error in the H-Cube that stopped the reaction some time during the night). The analysis of LCMS seemed to mainly show the desired product together with some starting material and a rather small by-product. It was concentrated in vacuo, and the residue was charged dry on silica gel (1 g) and purified by flash chromatography (Analogix, 40 g of S1O2, gradient of DCM to DCM / MeOH / NH40H 95/5 / 0.5 over 42 minutes) to give the 4-. { 4-amino-3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indole-5-yl] thieno [3,2-c] pyridin-7-yl} 1,1-Dimethylethyl -1-piperidinecarboxylate (91 mg) as an off-white solid. 3-G1 - (phenylacetin-2,3-dihydro-1 H-indol-5-ill-7- (4-piperidinyl) thieno [3,2-c1pyridin-4-amine] TFA (0.5 mL, 6.49 mmol) was added to a suspension of 4. { 4-amino-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] thieno [3,2-c] pyridin-7-yl} -1,1-dimethylethyl -1-piperidinecarboxylate (90 mg, 0.158 mmol) in dichloromethane (DCM) (3.5 ml), and the mixture was stirred at room temperature under nitrogen atmosphere for 30 min. Then, the reaction mixture was concentrated in vacuo, taken up in DCM, and passed through a resin cartridge-MP PL-HC03, rinsing with more DCM. The filtrate was concentrated in vacuo. The solid (labeled 96-A1) was not pure enough for shipping (impurities well visible by NMR), so the residue was purified by flash chromatography (Analogix, 24 g of Si02) gradient from DCM to DCM / MeOH / NH4OH 80/20/2 over 30 minutes) to give 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (4-piperidinyl) thieno [3 , 2-c] pyridin-4-amine (37 mg) as a white solid.

LC / MS (ES) m / z = 469 [+ H] +. 1 H NMR (400 MHz, DMSO-d 6) d 1, 64-1, 77 (m, 2 H), 1, 77-1, 86 (m, 2 H), 2.57-2.77 (m, 3 H), 3.07 (d, J = 12, 13 Hz, 2 H), 3.22 (t, J = 8.34 Hz, 2 H), 3.89 (s, 2 H), 4.24 (t, J = 8.59 Hz, 2 H), 5.24 (broad s, 2 H), 7.19-7.39 (m, 7 H), 7.41 (s, 1 H), 7 , 70 (s, 1 H), 8.15 (d, J = 8.34 Hz, 1 H) EXAMPLE 27 7- (3-r (dimethylamino) methyl-1-phenyl-3-ri- (phenylacetyl-2,3-dihydro-1H-indol-5-intienof3,2-c1pyridin-4-amine 3-. { 4-amino-3- [1- (phenylacetyl) -2,3-dihydro-H-indol-5-illthienof3,2-clpyridin-7-illbenzaldehyde A mixture of 7-iodo-3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine (100 mg, 0.196 mmol), 3-formylphenylboronic acid (40 mg, 0.267 mmol), and adduct of PdCl2 (dppf) -CH2Cl2 (9 mg, 0.01 mmol) in 1,4-dioxane (1.5 mL) and aqueous solution Saturated sodium bicarbonate (0.6 ml, 0.600 mmol) was degassed with nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120 ° C in the microwave for 30 min. The LCMS analysis showed the conversion complete and relatively clean of the desired product. The mixture was cooled, poured into water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The extracts were washed with brine (1 * 15 ml), dried (a2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g of S1O2, gradient of EtOAc in hexanes at 20% -100% over 35 minutes) to give the 3-. { 4-amino-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-7-yl} Benzaldehyde (66 mg, 0.135 mmol, 68.9% yield) as a brown solid. LC / MS (ES) m / z = 490 [M + H] +. 7- { 3 - [(di-methalamino) methyl-1-phenyl) -3-f1- (phenylacetin-2,3-dihydro-1 H-indol-5-illthieno [3,2-clpyridin-4-amine] Sodium triacetoxyborohydride (76 mg, 0.359 mmol) was added to a solution of 3-. { 4-amino-3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] t-ene [3,2-c] pyridin-7-yl} benzaldehyde (66 mg, 0.135 mmol), dimethylamine, 2.0 M in THF (0.10 mL, 0.200 mmol), and acetic acid (8 μ ?, 0.140 mmol) in 1,2-dichloroethane (DCE) ( 7 ml), and the mixture was stirred at room temperature under nitrogen atmosphere for 3 days. The LCMS analysis showed only starting material, so another portion of dimethylamine, 2.0 M in THF (0.20 ml, 0.400 mmol) and sodium triacetoxyborohydride (162 mg, 0.764 mmol) was added. Stirring was continued at room temperature for another 3.5 h, when the LCMS analysis showed complete conversion to the desired product. The mixture was poured into saturated aqueous NaHCO 3 solution (15 g. mi) and extracted with methylene chloride (2 x 15 ml). The extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson, C18, CH3CN solvent in water with 0.1% TFA, from 5% to 45%, 8 minutes). The product fractions were combined and concentrated in vacuo, and the residue was taken up in MeOH and passed through a resin cartridge MP PL-HC03, rinsing with more MeOH. The filtrate was concentrated in vacuo and dried in a vacuum oven overnight to give 7-. { 3 - [(dimethylamino) methyl] phenyl} -3- [1- (phenylacetyl) -2,3-dihydro-H-indol-5-yl] thieno [3,2-c] pyridin-4-amine (50 mg, 0.092 mmol, 67.9% yield ) in the form of a white solid. LC / MS (ES) m / z = 519 [M + H] +. H-NMR (400 MHz, DMSO-de) d 2.20 (s, 6 H), 3.24 (t, J = 8.34 Hz, 2 H), 3.47 (s, 2 H), 3, 90 (s, 2 H), 4.26 (t, J = 8.46 Hz, 2 H), 5.53 (broad s, 2 H), 7.23-7.30 (m, 2 H), 7.30 -7.39 (m, 6 H), 7.43-7.50 (m, 2 H), 7.51-7.56 (m, 1 H), 7.60 (s, 1 H) ), 7.90 (s, 1 H), 8, 18 (d, J = 8.34 Hz, 1 H).

EXAMPLE 28 3-f 1 -r (2,5-dimethylphenynacetin-2,3-dihydro-1 H -indol-5-yl) -1-methyl-1H-pyrazolof3,4-dTpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (65.3 mg, 0.192 mmol), acid (2,5-dimethylphenyl) acetic acid (31.6 mg, 0.192 mmol), HATU (73.2 mg, 0.192 mmol) in DF (2 ml) ) Hunig's base (0.134 ml, 0.770 mmol) was added. The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. It was filtered to give the product as a white solid. LC / MS (ES) m / z = 413.3 [M + H] +. H-NMR (400 MHz, DMSO-d6) d ppm 2.19 (s, 3 H), 2.25 (s, 3 H), 3.24-3.31 (m, 2 H), 3.84 ( s, 2 H), 3.94 (s, 3 H), 4.28 (t, J = 8.46 Hz, 2 H), 6.99 (s, 2 H), 7.08 (d, J) = 8.34 Hz, 1 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.52 (s, 1 H), 8.17 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 29 3- (1-r (3-fluoro-5-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-methyl-1H-pyrazolor-3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (65.3 mg, 0.192 mmol), (3-fluoro-5-methylphenyl) acetic acid (32.4 mg, 0.192 mmol), HATU (73.2 mg, 0.192 mmol) ) in DMF (2 ml) Hunig's base (0.134 ml, 0.77 mmol) was added. The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The solid was filtered to give the product as a white solid. The final product has approximately 0.7 equivalents of DMF. LC / MS (ES) m / z = 417.3 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 2.32 (s, 3 H), 3.22-3.99 (m, 2 H), 3.88 (s, 2 H), 3.93 ( s, 3 H), 4.24 (t, J = 8.59 Hz, 2 H), 6.92 (s, 1 H), 6.96 (d, J = 7.58 Hz, 2 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.51 (s, 1 H), 8.19 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 HOUR).

EXAMPLE 30 3-. { 1-r (3,5-dimethylphenylacetin-2,3-dihydro-1 H -indol-5-yl) -1-methyl-1H-pyrazolor-3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (70 mg, 0.206 mmol), acid (3,5-dimethylphenyl) acetic acid (31.0 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added to Hunig's base. (0.144 mL, 0.825 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The white solid was filtered to give the product. The final product has approximately 0.7 equivalents of DMF. LC / MS (ES) m / z = 413.3 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.26 (s, 6 H), 3.23 (s, 2 H), 3.79 (s, 2 H), 3.93 (s, 3 H) ), 4.21 (s, 2 H), 6.88-6.95 (m, 3 H), 7.45 (s, 1 H), 7.49 (s, 1 H), 8.20 ( d, J = 8.34 Hz, 1 H), 8.24 (s, 1 H).

EXAMPLE 31 5- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl) thienor-2,3-dlpyrimidin-4-amine 5-bromothieno [2,3-dlpyrimidin-4-amine] A suspension of 5-bromo-4-chlorothieno [2,3-d] pyrimidine (1 g, 4.01 mmol) in concentrated aqueous ammonium hydroxide solution (150 ml, 3852 mmol) was stirred overnight at 90 ° C in a sealed container. The reaction was allowed to cool to room temperature and filtered. The white solid in the filter was air-dried to provide 5-bromothieno [2,3-d] pyrimidin-4-amine (796 mg). LC / MS (ES) m / z = 387.1 [M + H] +. 5- (1-r (2,5-difluorophenyl) acetyl-2,3-dihydro-H-indol-5-yl) thienor-2,3-dlpyrimidin-4-amine To a mixture of 5-bromo-1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indole (150 mg, 0.426 mmol), bis (pinacolato) diboro (114 mg, 0.447 mmol ) and potassium acetate (125 mg, 1.285 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (17.39 mg, 0.021 mmol) was added and the reaction mixture was stirred for 3 hours at 100 ° C in a sealed container. The reaction was cooled to room temperature. 5-Bromothieno [2,3-d] pyrimidin-4-amine (103 mg, 0.447 mmol) and saturated aqueous solution of NaHCO 3 (2 mL) were added, and N 2 gas was bubbled through the mixture for 10 minutes. The adduct of PdCl2 (dppf) -CH2Cl2 (17.39 mg, 0.021 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 ° C. The mixture was poured into water and a precipitate formed. The mixture was filtered and the solid was taken up in a 20% CH3OH / CH2Cl2 mixture, and the resulting mixture was filtered, injected onto a 90 g silica gel column, and purified by flash chromatography (gradient: 100% hexanes to 100% EtOAc). The fractions containing the product were combined and concentrated to provide a solid. Trituration with Et.20 gave the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} Thieno [2,3-d] pyrimidin-4-amine (120 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) d 3,27 (t, 2 H), 3.96 (s, 2 H), 4.31 (t, J = 8.46 Hz, 2 H), 7, 13-7.32 (m, 4 H), 7.37 (s, 1 H), 7.43 (s, 1 H), 8.1 1 (d, J = 8.08 Hz, 1 H), 8.34 (s, 1 H).

EXAMPLE 32 3- (1-r (2,3-difluorophenyl) acetin-2,3-dihydro-1 H-indol-5-ylH-methyl-1 H-pyrazolor-3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidine -4-amine.2HCl (68 mg, 0.20 mmol), (2,3-difluorophenyl) acetic acid (34.5 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol) in DMF ( 2 ml) was added Hunig's base (0.14 ml, 0.802 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The solid was filtered to give the title compound as a white solid. The final product has approximately 0.7 equivalents of DMF. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.25-3.32 (m, 2 H), 3.94 (s, 3 H), 4.04 (s, 2 H), 4.32 ( t, J = 8.46 Hz, 2 H), 7.16 - 7.23 (m, 2 H), 7.33 - 7.40 (m, 1 H), 7.44 (d, J = 8 , 34 Hz, 1 H), 7.53 (s, 1 H), 7.96 (s, 1 H), 8.14 (d, J = 8.08 Hz, 1 H), 8.25 (s) , 1 HOUR).

EXAMPLE 33 7-methyl-5- (1-r (2-methylphenyl) acet ^ dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyr midin-4-amine.2HCl (70.6 mg, 0.209 mmol), (2-methylphenyl) acetic acid (31.4 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig base (0, 146 ml, 0.836 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a white solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and brought to dryness in the rotary evaporator to give a white solid. The solid was sonicated in water (10 mL), then filtered and dried to provide 7-methyl-5. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (48 mg) as a white solid. 1 H NMR (400 MHz, DMSO-cfe) d ppm 8.02-8.24 (m, 2 H), 7.32 (s, 1 H), 7.25 (s, 1 H), 7.12- 7.24 (m, 5 H), 6.07 (broad s, 2 H), 4.26 (t, J = 8.5 Hz, 2 H), 3.87 (s, 2 H), 3, 73 (s, 3 H), 3.24 (t, J = Q, 5 Hz, 2 H), 2.24 (s, 3 H).

EXAMPLE 34 5- (1-r (2-fluorophenynacetin-2,3-dihydro-1 H -indol-5-yl> -7-methyl-7H-pyrrolor-2,3-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indole-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimid N-4-amin.2HCl (70.6 mg, 0.209 mmol), (2-fluorophenyl) acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) ) Hunig's base (0.146 ml, 0.836 mmol) was added. The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The solid was filtered and dried to provide 5-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (73 mg). H-NMR (400 MHz, DMSO-d6) d ppm 3.26 (t, J = 8.72 Hz, 2 H), 3.73 (s, 3 H), 3.93 (s, 2 H), 4 , 28 (t, J = 8.46 Hz, 2 H), 7, 19 (d, J = 7.58 Hz, 3 H), 7.26 (s, 1 H), 7.30 - 7.38 (m, 3 H), 8.09 (d, J = 8.34 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 35 5- (1-R (3-fluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl> -7-methyl-7H-pyrrolor-2-dl-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pihmidin-4- amine.2HCl (70.6 mg, 0.209 mmol), (3-fluorophenyl) acetic acid (32.2 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base ( 0.166 mL, 0.836 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The solid was filtered and dried to provide the product as a white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.23 (t, J = 8.46 Hz, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4 , 19 - 4.26 (m, 2 H), 7.08 - 7.1 1 (m, 1 H), 7.12 - 7.17 (m, 2 H), 7.23 (d, J = 8.34 Hz, 1 H), 7.25 (s, 1 H), 7.31 (s, 1 H), 7.36 (s, 1 H), 7.39 (d, J = 6.82 Hz, 1 H), 8.10 - 8.17 (m, 2 H).

EXAMPLE 36 3- (1-r (2,3-difluorophenyl) acetyl-2,3-dihydro-1 H-indol-5-yl) thienor 3,2-clpyridin-4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2,3-difluorophenylacetic acid (56.7 mg, 0.329 mmol) and DIEA (0.261 mL, 1.496 mmol). N, N -dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine (31 mg). 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.12 (d, J = 8.1 Hz, 1 H), 7.85 (d, J = 6.1 Hz, 1 H), 7.59 ( s, 1 H), 7.44 (d, J = 6.1 Hz, 1 H), 7.32-7.41 (m, 2 H), 7.26 (d, J = 8.3 Hz, 1 H), 7, 14 - 7.24 (m, 2 H), 6.06 (d, J = 8.8 Hz, 2 H), 4.33 (t, J = 8.5 Hz, 2 H ), 4.04 (s, 2 H), 3.28 (t, 2 H).

EXAMPLE 37 7-methyl-5- (1-r (3-methylphenyl) acetin-2,3-dihydro-1 H-indol-5-yl> -7H-pyrrolor-2,3-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- Amine.2HCl (70.6 mg, 0.209 mmol), (3-methylphenyl) acetic acid (31.4 mg, 0.209 mmol), HATU (79 mg, 0.209 mmol) in DMF (2 mL) was added Hunig's base ( 0.166 mL, 0.836 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a light brown solid formed. The solid was filtered and dried to provide 7-methyl-5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (57 mg). H NMR (400 MHz, DMSO-cfe) d ppm 2.30 (s, 3 H), 3.16 - 3.23 (m, 2 H), 3.72 (s, 3 H), 3.82 ( s, 2 H), 4.17-4.24 (m, 2 H), 7.06-7.14 (m, 3 H), 7.20-7.27 (m, 3 H), 7, 30 (s, 1 H), 8.1-1.8.18 (m, 2 H).

EXAMPLE 38 3- (1 -3-fluoro-2-methylphenyl) acet'n-2,3-dihydro-1 H-indol-5-yl > thienor3,2- clpyridin-4-amine Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.329 mmol) followed by HATU (125 mg, 0.329 mmol), 3-fluoro-2-methylphenylacetic acid (55.4 mg, 0.329 mmol) and DIEA (0.230 mL, 1.317 mmol). N, N-dimethylformamide (DMF) (2 ml) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine (94.6 mg). 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.12 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 5.8 Hz, 1 H), 7.41 ( s, 1 H), 7.35 (s, 1 H), 7.26 (d, J = 5.6 Hz, 1 H), 7.14 - 7.25 (m, 2 H), 7.02 - 7.1 1 (m, 2 H), 5.42 (broad s, 2 H), 4.31 (t, J = 8.5 Hz, 2 H), 3.97 (s, 2 H), 3.27 (t, 2 H), 2.15 (m, 3 H).

EXAMPLE 39 3- (2-r5- (4-aminotienor3.2-clpiridin-3-yl) -2.3-dihydro-1 H-indol-1-in-2-oxoetiDenzonitrile Into a 4 ml vial with screw cap was added 3- (2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine (100 mg, 0.329 mmol) followed by HATU (125 mg, 0.329 mmol), 3-cyanophenylacetic acid (53.0 mg, 0.329 mmol) and DIEA (0.230 mL, 1.317 mmol). The?,? - dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and allowed to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organic extracts were dried over Na 2 SO 4 and concentrated. The residue was taken up in DCM and purified by normal phase chromatography (MeOH / 0-10% DCM). The fractions were collected and concentrated to provide 3-. { 2- [5- (4-aminothieno [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indol-1-yl] -2-oxoethyl} benzonitrile (100.8 mg). 1 H NMR (400 MHz, DMSO-de) d ppm 8.13 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 5.8 Hz, 1 H), 7.73 - 7.79 (m, 2 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.52-7.61 (m, 1 H), 7.44 (s, 1 H), 7.35 (s, 1 H), 7.28 (d, J = 5.6 Hz, 1 H), 7.20-7.26 (m, 1 H), 5.48 (s) width, 2 H), 4.29 (t, J = 8.5 Hz, 2 H), 4.00 (s, 2 H), 3.27 (t, 2 H).

EXAMPLE 40 3-f 1 -r (2-fluoro-5-methylphenyl) acetin-2,3-dihydro-1 H -indol-5-ylM-methyl-1 H-pyrazolor-3,4-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidi n-4-amin.2HCl (70 mg, 0.206 mmol), (2-fluoro-5-methylphenyl) acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 g. mi) was added Hunig's base (0.144 ml, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound as an off-white solid. NMR1H (400 MHz, DMSO-de) d ppm 2.29 (s, 3 H), 3.28 (t, J = 8.46 Hz, 2 H), 3.89 (s, 2 H), 3, 93 (s, 3 H), 4.29 (t, J = 8.46 Hz, 2 H), 7.07 (s, 1 H), 7.09 - 7.16 (m, 2 H), 7 , 43 (d, J = 8.34 Hz, 1 H), 7.52 (s, 1 H), 8.15 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 41 3-f 1 -r (2,3-dimethylpheninacetin-2,3-dihydro-1 H -indol-5-ylM-methyl-1H-pyrazolor-3,4-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (70 mg, 0.206 mmol), (2,3-dimethylphenyl) acetic acid (33.9 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO- / 6) d ppm 2.12 (s, 3 H), 2.27 (s, 3 H), 3.24-3.31 (m, 2 H), 3.91 (s, 2 H), 3.94 (s, 3 H), 4.24 - 4.32 (m, 2 H), 7.03 (d, J = 6.82 Hz, 2 H), 7, 05-7.09 (m, 1 H), 7.43 (d, J = 8.34 Hz, 1 H), 7.52 (s, 1 H), 8.17 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 42 3-? -r (3-chlorophenyl) acet-2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H-pyrazolor3.4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H-pyrazolo [3,4-d] pinmidin -4-amine.2HCl (70 mg, 0.206 mmol), (3-chlorophenyl) acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound as an off-white solid. The final product has approximately 0.5 equivalents of DMF. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.28 (s, 2 H), 3.94 (s, 5 H), 4.26 (t, J = 8.59 Hz, 2 H), 7 , 28 (d, J = 7.33 Hz, 1 H), 7.35-7.41 (m, 3 H), 7.44 (d, J = 9.85 Hz, 1 H), 7.52 (s, 1 H), 8.18 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 43 1 - . 1-methyl-3- (1- r3- (trifluoromethyl) phenynacetyl 2,3-dihydro-1H-indol-5-i pyrazolor3,4-d1pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (70 mg, 0.206 mmol), [3- (trifluoromethyl) phenyl] acetic acid (42.1 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added. Hunig (0.144 ml, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give 1-methyl-3- (1 - { [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) -1 H -pyrazolo [3,4-d] pyrimidin-4-amine in the form of an off-white solid. The final product has approximately 0.7 equivalents of DMF. LC / MS (ES) m / z = 453, 1 [M + H] +. 1 H NMR (400 MHz, DMSO-cf 6) d ppm 3.25-3.32 (m, 2 H), 3.94 (s, 3 H), 4.05 (s, 2 H), 4.29 ( t, J = 8.46 Hz, 2 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.52 (s, 1 H), 7.59-7.66 (m, 3 H), 7.69 (s, 1 H), 8, 17 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 44 7-methyl-5- (1-fr3- (trifluoromethyl) phenyl-1-acetyl-V2,3-dihydro-1H-indo ^ pyrrolor2,3-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- Amine.2HCl (70.6 mg, 0.234 mmol), [3- (trifluoromethyl) phenyl] acetic acid (47.8 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. of Hunig (0.163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a whitish solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and evaporated to dryness to give a white solid, which still had some starting material. The solid was treated with sonication in water (10 ml), then filtered and dried to give 7-methyl-5- (1 - { [3- (trifluoromethyl) phenyl] acetyl] -2.3 -dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as an off-white solid. . LC / MS (ES) m / z = 452.1 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.25 (t, J = 8.34 Hz, 2 H), 3.74 (s, 3 H), 4.03 (s, 2 H), 4 , 27 (t, J = 8.59 Hz, 2 H), 7.22 (m, 1 H), 7.28-7.35 (m, 2 H), 7.58-7.66 (m, 3 H), 7.68 (s, 1 H), 8.12 (d, J = 8.08 Hz, 1 H), 8.17 (s, 1 H).

EXAMPLE 45 5- (1-Rf3-fluoro-5-methylphenyl) acetin-2,3-dihydro-1 H-indol-5-yl-methyl-7H-pyrrolor-2,3-dlpyrimidin-4-amine To a suspension of 5- (2,3-dihydro-1 H -indole-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine, 2 HCl salt (200 mg 0.59 mmol, 1 equiv) and HATU (247 mg, 0.65 mmol, 1.1 equiv) in 2 ml of DMF was added DIEA (0.36 ml, 2.07 mmol, 3.5 equiv) in a portion. The mixture became a clear but dark-toned solution, to which (3-fluoro-5-methylphenyl) acetic acid (70 mg, 0.42 mmol, 0.7 equiv) was added as a solid. The reaction mixture was stirred at room temperature for 18 hours. Water (15 ml) was added to the mixture to give a precipitate, which leaked. The filter cake was washed with water and dried with a laboratory vacuum system for 20 h. The yellowish solids were dissolved in MeOH in 10% DCM, and absorbed in a dry-loaded cartridge. Purification was done on a silica gel cartridge SF15-24 g using gradient elution of A in 1% EtOAc at 100% A (A was a mixture of MeOH in 9% EtOAc, gradient: 0-5 min. , A at 1%, 5-15 min, A at 1-100%, 15-60 min, A at 100%). The combined fractions were concentrated in vacuo to give a suspension (2 mL), which was cooled for 1 h, followed by filtration. The solids were washed with cold MeOH (3 mL), MTBE (2 × 3 mL) and then hexane (2 × 3 mL). The solids were dried under vacuum at 65 ° C for 20 h to give the 5-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (97 mg) in the form of light beige solids. LC-MS (ES) m / z = 416 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.32 (s, 3 H), 3.22 (t, J = 8.46 Hz, 2 H), 3.73 (s, 3 H), 3 , 86 (s, 2 H), 4.21 (t, J = 8.46 Hz, 2 H), 5.93 -6.21 (broad s, 1.4 H), 6.90 - 6.99 (m, 3 H), 7.23 (d, J = 12.0 Hz, 1 H), 7.25 (s, 1 H), 7.31 (s, 1 H), 7, 12 (d, J = 8.0 hz, 1 H), 8, 14 (s, 1 H).

EXAMPLE 46 5- (1-r (3-chlorophenylacetin-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolor-2,3-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), (3-chlorophenyl) acetic acid (39.9 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base ( 0.163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a purple solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and evaporated to dryness to give a purple solid, which still had some starting material. The solid was treated with sonication in water (10 ml), then filtered and dried to provide 5-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine as a purple solid. 1 H-NMR (400 MHz, DMSO-Q6) d ppm 3.24 (t, J = 8.59 Hz, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4 , 23 (t, J = 8.46 Hz, 2 H), 6.10 (s, 2 H), 7.23 (d, J = 8.34 Hz, 1 H), 7.26 - 7.29 (m, 2 H), 7.31-7.33 (m, 1 H), 7.34-7.39 (m, 3 H), 8.12 (d, J = 8.34 Hz, 1 H ), 8.15 (s, 1 H).

EXAMPLE 47 5- (1-r (2-chlorophenyl) acetin-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolor-2,3-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), (2-chlorophenyl) acetic acid (39.9 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base ( 0.163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured in water (100 ml) and a whitish solid formed. The solid was filtered and dried to provide 5-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine as an off-white solid. The NMR analysis showed that it has 0.8 eq of DMF. 1 H NMR (400 MHz, D SO-efe) d ppm 3.39 (m, 2 H), 3.73 (s, 3 H), 4.00 (s, 2 H), 4.29 (m, 2) H), 7.25 (m, 2 H), 7.30-7.36 (m, 3 H), 7.40 (d, J = 4.55 Hz, 1 H), 7.46 (s, 1 H), 8.09 (s, 1 H), 8.14 (s, 1 H).

EXAMPLE 48 7-methyl-5- (1 - (r2- (methyloxy) phenynacetyl> -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolor-2,3-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), [2- (methyloxy) phenyl] acetic acid (38.9 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. of Hunig (0.163 mL, 0.936 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a purple solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and evaporated to dryness to give a purple solid, which still had some starting material. The solid was sonicated in water (10 mL), then filtered and dried to provide the title compound, 7-methyl-5- (1- {[2- (methyloxy) phenyl] acetyl}. -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pinmidin-4-amine, in the form of a light brown solid (22 mg). 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.23- 3.26 (m, 2 H), 3.73 (s, 3 H), 3.78 (s, 5 H), 4.23 ( m, 2 H), 6.06 (broad s, 2 H), 6.89 - 6.96 (m, 1 H), 7.00 (d, J = 8.34 Hz, 1 H), 7, 18 -7.25 (m, 4 H), 7.31 (s, 1 H), 8, 10 (d, J = 8.08 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 49 1 - . 1-methyl-3- (1-f r3- (methyloxy) phenMacetyl) -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolor-3,4-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (70 mg, 0.206 mmol), [3- (methyloxy) phenyl] acetic acid (34.3 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the product as an off-white solid. The final product has approximately 0.5 equivalents of DMF. LC-MS (ES) m / z = 415.3 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 3.22 (m., 2 H), 3.75 (s, 3 H), 3.86 (s, 2 H), 3.93 (s, 3 H), 4.19 - 4.26 (m, 2 H), 6.84 (d, J = 8.34 Hz, 2 H), 6.87 - 6.94 (m, 2 H), 7, 26 (t, J = 8.08 Hz, 1 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.50 (s, 1 H), 8.20 (d, J = 8.34 Hz, 1 H), 8.24 (s, 1 H).

EXAMPLE 50 7-methyl-5- (1- (r3- (methyloxy) phenynacetyl > -2,3-dhydro-1 H -indol-5-yl) -7H-pyrrolor-2,3-d-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), [3- (methyloxy) phenyl] acetic acid (38.9 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. of Hunig (0.163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered and dried to give 7-methyl-5- (1- {[[3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine as an off-white solid (91 mg). 1 H NMR (400 MHz, DMSO-cf 6) d ppm 3.21 (t, J = 8.46 Hz, 2 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 3.84 (s, 2 H), 4.20 (t, = 8.46 Hz, 2 H), 6.06 (broad s, 2 H), 6.82 - 6.90 (m, 3 H), 7, 21-7.26 (m, 3 H), 7.28-7.31 (m, 1 H), 8, 1 1 - 8, 19 (m, 1 H), 8.14 (s, 1 H) .

EXAMPLE 51 3-f 1 -r (2-chlorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H-pyrazolors ^ -dlpyrimidin -amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-H-pyrazolo [3,4-d] pyrimidine-4- Amine.2HCl (70 mg, 0.206 mmol), (2-chlorophenyl) acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0, 144 ml, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine as an off-white solid. 1 H NMR (400 MHz, DMSO-c / 6) d ppm 3.28-3.30 (m, 2 H), 3.94 (s, 3 H), 4.02 (s, 2 H), 4, 32 (t, = 8.46 Hz, 2 H), 7.31-7.37 (m, 2 H), 7.40-7.45 (m, 2 H), 7.46-7.49 (m, 1 H), 7.53 (s, 1 8) , 15 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 52 1 - . 1 -methyl-3-? 1 - (r 2 -methyl-oxy) phenynacetyl > -2.3-dihydro-1 H-indol-5-yl) -1 H- pyrazolor3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4 -amine.2HCl (70 mg, 0.206 mmol), [2- (methyloxy) phenyl] acetic acid (34.3 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig base (0.144 ml, 0.825 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound (78 mg) as an off-white solid. H-NMR (400 MHz, DMSO-de) d ppm 3.28 (m, 2 H), 3.78 (s, 3 H), 3.80 (s, 2 H), 3.94 (s, 3 H) ), 4.22 - 4.30 (m, 2 H), 6.93 (t, J = 7.45 Hz, 1 H), 7.01 (d, J = 7.83 Hz, 1 H), 7.20 (dd, = 7.58, 1.52 Hz, 1 H), 7.25-7.32 (m, 1 H), 7.43 (d, J = 8.34 Hz, 1 H) , 7.51 (s, 1 H), 8, 16 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 53 5- 1-r (3-chloro-5-fluorophenyl) acet'n-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolof2.3-d1pyrimidin-4- amine To a suspension of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyridin-4-amine, salt of 2HCl (200 mg, 0.59 mmol, 1 equiv) and HATU (247 mg, 0.65 mmol, 1.1 equiv) in 2 mL of DMF was added DIEA (0.36 mL, 2.07 mmol, 3%). , 5 equiv) in one portion. The mixture became a clear but dark-toned solution, to which (3-chloro-5-fluorophenyl) acetic acid (60 mg, 0.59 mmol) was added as a solid. After 1.5 h, another 30 mg of the acid was added. After 30 min, the resulting suspension was diluted with 15 ml of water. The aqueous suspension was filtered and the filter cake was washed with water, and dried with a laboratory vacuum system. This solid was dissolved in MeOH in 10% DCM (did not completely dissolve, part was charged as suspension) and absorbed in a dry loaded cartridge. Purification was done on a 24 g silica gel cartridge using gradient elution of A in 1% EtOAc at 100% A (A was a mixture of MeOH in 9% EtOAc, gradient: 0-5 min, A at 1%, 5-15 min, A at 5-100%, 15-60 min, A at 100%). The desired fractions were combined and concentrated in vacuo to give a solid residue, which after standing for 10 min developed a light brown color. The residue was taken up in CHCl3 (1 mL) and MTBE (6 mL) to give a suspension that was filtered. The light brown filter cake was washed with MTBE (3 mL) and hexane (2x 3 mL), and dried under vacuum at 65 ° C for 20 h to give (93 mg) as a light brown solid. . LC-MS (ES) m / z = 436 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe + 2 drops of TFA) d ppm 3.25 (t, J = 8.2 Hz, 2 H), 3.84 (s, 3 H), 3.96 (s, 2 H), 4.25 (t, J = 8.5 Hz, 2 H), 7, 17 (d, J = 9.6 Hz, 1 H), 7.23-7.29 (m, 2 H ), 7.30-7.37 (m, 2 H), 7.61 (s, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 8.47 (s, 1 H).

EXAMPLE 54 3- (1-f (2,5-difluorophenylacetyl) -2,3-dihydro-1 H-indol-5-yl furof3,2-c1pyridin 5- (4-aminofuro [3,2-clpiridin-3-yl) -2,3-dihydro-1 H -indole-1-carboxylate A mixture of 3-bromofuro [3,2-c] pyridin-4-amine (3.002 g, 0.09 mmol), 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-) il) -2,3-dihydro-1 H-indole-1,1-dimethylethyl carboxylate (5.346 g, 15.48 mmol), and adduct of PdCl2 (dppf) -CH2Cl2 (0.573 g, 0.702 mmol) in 1,4-dioxane (120 ml) and saturated aqueous sodium bicarbonate solution (43 ml, 43.0 mmol) was degassed with nitrogen for 20 minutes. The reaction mixture was then stirred under reflux under a nitrogen atmosphere for 16 hours. It was then cooled, poured into semi-saturated aqueous NaHCO 3 solution (250 ml), and extracted with ethyl acetate (2 * 250 ml). The extracts were washed with brine (1? 250 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 400 g of S1O2, gradient of EtOAc in hexanes to 20% -100% over 60 minutes, then EtOAc to 100% for 15 minutes more) to give the 5- (4 α-Aminophuro [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (3.93 g) as an off-white solid. LC / MS (ES) m / z = 352 [M + Hf. 3- (2,3-dihydro-1 H-indol-5-yl) furor3.2-clpyridin-4-amine A mixture of 5- (4-aminofuro [3,2-c] pyridin-3-yl) - 2,3-Dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (1.04 g, 2.96 mmol) and HCl, 4.0 M in dioxane (15 mL, 60.0 mmol) were added. stirred at room temperature under nitrogen atmosphere for 4.5 h. Then, the reaction mixture was concentrated in vacuo to give 3- (2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (973 mg, 2, 85 mmol, 96% yield), dihydrochloride (2HCl), as an off-white solid. LC / MS (ES) m / z = 252 [M + H] +. 3-. { 1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl > furor3,2-clpyridin-4-amine A mixture of 3- (2,3-dihydro-1 H -indole-5-yl) furo [3,2-c] pi din-4-amine 2HCI (688 mg, 2.016 mmol), acid 2, 5-difluorophenylacetic acid (354 mg, 2.057 mmol), HATU (844 mg, 2.220 mmol), and Hunig's base (1.4 mL, 8.02 mmol) in NN-dimethylformamide (DMF) (15 mL) was stirred at room temperature. atmosphere for 17 h. HPLC analysis indicated complete conversion, whereby the mixture was poured into water (75 ml), the suspension was stirred for approximately 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction to give 3- . { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (834 mg, 2.057 mmol, 102% yield) as a brown solid. LC / MS (ES) m / z = 406 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.29 (t, J = 8.34 Hz, 2 H), 3.96 (s, 2 H), 4.31 (t, J = 8.46 Hz) , 2 H), 5.52 (s, 2 H), 6.93 (d, J = 5.81 Hz, 1 H), 7.14-7.34 (m, 4 H), 7.41 ( s, 1 H), 7.87 (d, J = 5.81 Hz, 1 H), 7.92 (s, 1 H), 8.13 (d, J = 8.08 Hz, 1 H).

EXAMPLE 55 1-methyl-3- (1-r (2,3,5-trifluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl) -1H-pyrazolor-3,4-d-pyrimidin-4-amine A solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-amine (100 mg, 0.330 mmol), (2,3,5-trifluorophenyl) acetic acid (69.1 mg, 0.363 mmol), HATU (151 mg, 0.396 mmol), DIEA (0.173 mL, 0.991 mmol) was stirred overnight at room temperature. At this time, the LCMS analysis indicated complete conversion, whereby the reaction mixture was poured into water (10 ml), whereby a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and charged dry on silica, then purified by flash chromatography (methanol in 0-10% DCM) to give 1-methyl-3-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine (72 mg) as a white solid. LC-MS (ES) m / z = 439 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) 3.26-3.32 (m, 2 H), 3.94 (s, 3 H), 4.06 (s, 2 H), 4.28-4, 37 (m, 2 H), 7.09-7.20 (m, 1 H), 7.41-7.52 (m, 2 H), 7.53-7.57 (m, 1 H), 8.11-8.18 (m, 1 H), 8.25 (s, 1 H).

EXAMPLE 56 5-. { 1-r (2,5-dimethyphenyl) acetun-2,3-dihydro-1H-indol-5-yl 7-methyl-7H-pyrrolor-2,3-d] pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- Amine HCl (70.6 mg, 0.234 mmol), acid (2,5-dimethylphenyl) acetic acid (38.4 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. Hunig (0. 163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a purple solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and evaporated to dryness to give an off white solid, which still had some starting material. The solid was sonicated in water (10 ml) at 50 ° C, then filtered and dried to give the title compound as a brown solid. 1 H-NMR (400 MHz, DMSO-d 6) d ppm 2.19 (s, 3 H), 2.25 (s, 3 H), 3.24 (m, 2 H), 3.73 (s, 3 H) , 3.82 (s, 2 H), 4.25 (t, J = 8.21 Hz, 2 H), 6.12 (broad s, 2 H), 6.94 - 7.01 (m, 2 H), 7.07 (d, J = 7.58 Hz, 1 H), 7.20-7.28 (m, 2 H), 7.32 (s, 1 H), 8.11 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 57 3- (1-r (2,5-difluorophenyl) acet'n-2,3-dihydro-1 H-indol-5-yl) -7- (1 H -pyrazol-4-yl) furor 3,2-c1pyridin -4-amine 3- (1-α- (2,5-difluorophenyl) acetyl-2-dihydro-1 H -indol-5-yl) -7-yodofurof3,2-c1pyridin-4-amine A solution of NIS (147 mg, 0.653 mmol) in DMF (3 mL) was added dropwise to a solution of 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (257 mg, 0.634 mmol) in DMF (3.5 ml) at -40 ° C, and the mixture was stirred and allowed to slowly warm to room temperature (the temperature it was still <-10 ° C after 2 hours, and the reaction had advanced to approximately 20% according to the HPLC analysis). After 18 hours, the HPLC analysis indicated the complete consumption of the starting material and only a small amount of the diiodine by-product had formed. The reaction mixture was poured into water (35 ml), stirred for approximately 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction for several hours to give 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- iodofuro [3,2-c] pyridin-4-amine (253 mg) as a brown solid. LC / MS (ES) m / z = 532 [M + H] +. 3- (1-r (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl) -7- (1 H -pyrazol-4-yl) furo [3,2-c1pyridin-4-amine] A mixture of 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodofuro [3,2-c] pyridin-4-amine (142 mg, 0.267 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (1 18 mg, 0.401 mmol) and PdCl2 adduct (dppf) -CH2Cl2 (13 mg, 0.016 mmol) in 1,4-dioxane (3 mL) and saturated aqueous sodium bicarbonate solution (0.80 mL, 0.800 mmol) was degassed with nitrogen for 10 minutes in a vial of microwave. The vial was then capped and the mixture was stirred at 120 ° C in the microwave for 30 min. The LCMS analysis showed the complete conversion to the des-Boc product. The mixture was cooled, poured into semisaturated aqueous solution of NaHCO3 (25 mL), and extracted with ethyl acetate (2.25 mL). The extracts were washed with brine (1 * 25 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, gradient of EtOAc in hexanes 50% -100% over 10 minutes, then EtOAc for 5 minutes, then MeOH in 0-10% EtOAc throughout 20 minutes) to give the 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-4-yl) furo [3,2-c] pyridin-4-amine (121 mg, 0.244 mmol, 91% yield) as a white solid. LC / MS (ES) m / z = 472 [M + Hf. 1 H NMR (400 MHz, DMSO-d 6) 8 3.29 (t, J = 8.34 Hz, 2 H), 3.97 (s, 2 H), 4.31 (t, J = 8.46 Hz, 2 H), 5.49 (s, 2 H), 7.15-7.30 (m, 3 H) , 7.33 (d, J = 8.08 Hz, 1 H), 7.44 (s, 1 H), 7.99-8.10 (m, 2 H), 8, 13 (d, J = 8.08 Hz, 1 H), 8.17 - 8.29 (m, 2 H), 13.01 (broad s, 1 H).

EXAMPLE 58 3- (1-r (3,5-nichlorophenacetm-2,3-lydro-1 H -indol-5-yl) -1-methyl-1 H-pyrazolor-3,4-d-pyrimidin-4-amine A solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (89 mg, 0.293 mmol), (3,5-Dichlorophenyl) acetic acid (60 mg, 0.293 mmol), HATU (11 mg, 0.293 mmol), DIEA (0.204 mL, 1.171 mmol) was stirred overnight at room temperature. The crude product was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried in the pump for 30 minutes. The crude product was adsorbed on silica and purified by flash chromatography (methanol in 0-10% DCM), concentrated and dried overnight in a vacuum oven to provide 3-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (80 mg) as a white solid. LCMS (ES) m / z = 453, 455 [M + H] +. H-NMR (400 MHz, DMSO-d6) d 3.29 (t, J = 9.60 Hz, 2 H), 3.94 (s, 3 H), 3.97 (s, 2 H), 4, 26 (t, J = 8.59 Hz, 2 H), 7.40 (d, J = 2.02 Hz, 2 H), 7.45 (d, J = 8.08 Hz, 1 H), 7 , 53 (d, J = 1, 77 Hz, 2 H), 8, 17 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 59 5- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H -indol-5-ylV7-methyl-7H-pyrrolof2,3-d1-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (200 mg, 0.663 mmol), acid (2,5-diluorophenyl) acetic acid (120 mg, 0.696 mmol), HATU (265 mg, 0.696 mmol) in DMF (5 mL) was added Hunig's base (0.463 mL) 2.65 mmol). The mixture was stirred at room temperature overnight. The LCMS analysis showed that the reaction was complete. The reaction was poured into water and a white solid formed. The solid was filtered and dried to provide 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine as a white solid. The NMR analysis showed that there is 1 eq. of DMF in the compound. LCMS (ES) m / z = 420 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.27 (t, J = 8.46 Hz, 2 H), 3.74 (s, 3 H), 3.95 (s, 2 H), 4 , 29 (t, J = 8.46 Hz, 2 H), 6.05 (broad s, 2 H), 7.21 - 7.27 (m, 5 H), 7.34 (s, 1 H) , 8.09 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 60 3- (1-r (2-difluorophenyl) acet'n-2,3-dihydro-1 H-indol-5-yl.} - 7 - (1 H -pyrazol-4-yl) thienor 3,2-c-pyridin- 4-amine In a 25 ml pressure tube of microwave reactor, 3- were charged. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodothieno [3,2-c] pyridin-4-amine (129 mg, 0.236 mmol), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 1 H-pyrazole-1-carboxylate of 1, -dimethylethyl (69.3 mg, 0.236 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride complex (II) -dichloromethane 9.62 mg, 0.012 mmol), and saturated aqueous sodium carbonate solution (0.707 ml, 0.707 mmol) followed by dioxane (5 ml). The reaction was heated at 120 ° C for 40 min in a microwave reactor. The reaction was cooled to room temperature, the mixture transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and greasy black solid remaining in the tube, a total of 100 ml of EtOAc to the mixture. The EtOAc solution was evaporated to dryness, and redissolved at 0? 2? 2 /? ß0? (8 ml / 2 ml). Purify by flash column with 25-100% EtOAc / hexane, then 0-10% MeOH / EtOAc, Si SF15-24 g, to give a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-4-yl) thieno [3 c] pyridin-4-amine (40 mg) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.24 - 3.29 (m, 2 H), 3.97 (s, 2 H), 4.32 (t, J = 8.46 Hz, 2 H), 5.40 (s, 2 H), 7, 18 - 7.21 (m, 1 H), 7.23-7.29 (m, 3 H), 7.38 (s, 1 H) , 7.49 (s, 1 H), 7.96 (s, 1 H), 8.07 (s, 1 H), 8.12 (d, J = 8.34 Hz, 2 H), 13, 09 (s, 1 H) EXAMPLE 61 3-f 1 -f (3,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H-pyrazolor-3,4-d-pyrimidin-4-amine A solution of 3- (2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-amine (150 mg, 0.495 mmol ), (3,5-difluorophenyl) acetic acid (85 mg, 0.495 mmol), HATU (188 mg, 0.495 mmol), DIEA (0.346 mL, 1.982 mmol) was stirred at room temperature throughout the end of week. At this time, LC S analysis indicated complete conversion, whereby the reaction mixture was poured into water (10 ml), whereby a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and charged dry on silica, then purified by flash chromatography (methanol in 0-10% DCM) to provide 3-methyl-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (150 mg, 0.357 mmol, 72.0% yield) as a white solid. LC-MS (ES) m / z = 421 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.27 (m, 2 H), 3.94 (s, 3 H), 3.97 (s, 2 H), 4.18 - 4.32 (m , 2 H), 7.02-7.09 (m, 2 H), 7, 11-7.20 (m, 1 H), 7.41-7.47 (m, 1 H), 7.50 - 7.55 (m, 1 H), 8.12 - 8.22 (m, 1 H), 8.25 (s, 1 H). Note: NHs are not observed as individual peaks.

EXAMPLE 62 5- (1-r (3-methylphenyl) acetin-2,3-dihydro-1H-indol-5-ylV7- (4-piperidinin-7H-pyrrolof2,3-cnpyrimidin-4-amine In a 350 ml hermetically sealed tube, to 5-bromo-1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 / - / - indole (13.57 g, 41.1 mmol), bis (p -nacolato) diboron (12.52 g, 49.3 mmol) and potassium acetate (12.10 g, 123 mmol) was added 1,4-dioxane (200 mL) and the mixture was degassed with N2 for 10 minutes. minutes The adduct of PdCl2 (dppf) -CH2Cl2 (1.678 g, 2.055 mmol) was added and the reaction mixture was stirred for 48 hours at 100 ° C. The LCMS analysis showed no more starting material. The mixture was cooled to room temperature. Ethyl acetate (500 ml) was poured into the mixture and then the mixture was filtered. The filtrate was poured into a separating funnel. Washed with brine, dried (MgSO.sub.4), filtered and concentrated, and purified by Analogix Si90 silica, gradient of 0-40% EtOAc / hexane to give 1 - [(3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (8.35 g) as a white solid. LC-MS (ES) m / z = 378.3 [M + H] +.

To 4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (5 g, 32.6 mmol) in chloroform (100 mL) was added NBS (6.08 g, 34.2 mmol), and the reaction mixture was stirred at 70 ° C for 3 hours. The reaction was allowed to cool to room temperature, and the mixture was filtered, washing the solid with additional CHCl3 to give 5-bromo-4-chloro-1 H-pyrrolo [2,3-d] pyrimidine as an off-white solid .

To a solution of 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (214 mg, 0.921 mmol), 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (556 mg, , 76 mmol) and triphenylphosphine (483 mg, 1.841 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (0.291 mL, 1.841 mmol). The solution was stirred at room temperature. After 2 h the reaction was concentrated and then loaded onto a 25 g Biotage SNAP column to give 4- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate of 1, -dimethylethyl (330 mg, 86% yield) as a white solid. H NMR (400 MHz, DMSO-d6) d 8.68 (s, 1 H), 8.23 (s, 1 H), 4.83-4.97 (m, 1 H), 4.1 1 ( s wide, 2H), 2.95 (broad s, 2H), 1, 84 - 2.05 (m, 4H), 1, 43 (s, 9H) To 4-1-dimethylethyl 4- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate (313 mg, 0.753 mmol) was added ammonium hydroxide ( 2 ml, 51.4 mmol) and 1,4-dioxane (1 ml) in a 5 ml microwave vial and heated in a microwave for 20 min at 100 ° C. After 35 total minutes, the reaction was complete. The reaction was concentrated to give the 4- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate 1,1-dimethylethyl ether (336 mg). 1 H NMR (400 MHz, DMSO-d 6) d 8.09 (s, 1 H), 7.60 (s, 1 H), 4.71 (tt, J = 5.40, 10.64 Hz, 1 H ), 4.08 (broad s, 2H), 2.91 (broad s, 2H), 1, 81-1, 94 (m, 4H), 1, 43 (s, 9H).

To the 1,1-dimethylethyl 4- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate (200 mg, 0.505 mmol) and 1 - [( 3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1H-indole (228 mg, 0.606 mmol) dissolved in 1,4-dioxane (4 mL) was added saturated aqueous solution of NaHCO 3 (2 mL). The mixture was then bubbled with N 2 gas for 10 minutes and then Pd (Ph 3 P) 4 (58.3 mg, 0.050 mmol) was added and then bubbled for an additional 5 minutes. The reaction was then capped and heated at 100 ° C overnight. The The mixture was allowed to cool and then diluted with water (10 mL) then extracted with EtOAc (3x20 mL). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to isolate an amber oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with hexane and eluting with a gradient of 0 to 10% MeOH in DCM for 30 minutes to provide the 4- (4-amino-5-. [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} - 7 H -pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate 1, 1-dimethylethyl (230 mg, 80% yield) in the form of an amber oil. 1 H NMR (400 MHz, DMSO-de) d 8.14 (s, 1 H), 8.13 (s, 1 H), 7.45 (s, 1 H), 7.32 (s, 1 H) , 7.20-7.26 (m, 2H), 7.12 (s, 1 H), 7.09 (t, J = 7.58 Hz, 2H), 4.71 - 4.83 (m, 1 H), 4.20 (t, J = 8.46 Hz, 2H), 4.08 - 4.15 (m, 2H), 3.94 (s, 2H), 3.82 (s, 2H) , 3.20 (t, J = 8.46 Hz, 2H), 2.95 (broad s, 2H), 2.31 (s, 3H), 1, 86-1, 97 (m, 4H), 1 , 43 (s, 9H).

To 4- (4-amino-5- { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} - 7 H -pyrrolo [2,3- d] pyrimidin-7-yl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (230 mg, 0.406 mmol) were added 1,4-dioxane and 4 N HCl in dioxane (4 mL, 16.00 mmol). The mixture was allowed to stir overnight at 50 ° C. The reaction was concentrated. The solid was sonicated with hexane: DCM 1: 1 and the solid isolated by filtration to isolate the 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (188 mg, 80% yield) as a white solid, such as the trihydrochloride salt. LC-MS (ES) m / z = 467.4 [M + H] +. 1 H NMR (400 MHz, methanol-d 4) d 8.38 (s, 1 H), 8.29 (d, J = 8.34 Hz, 1 H), 7.61 (s, 1 H), 7.41 (s, 1 H), 7.35 (dd, J = 1, 77, 8 , 34 Hz, 1 H), 7.22 - 7.28 (m, 1 H), 7, 18 (s, 1 H), 7, 13 (t, J = 7.33 Hz, 2H), 5, 07 - 5.18 (m, 1 H), 4.25 (t, J = 8.46 Hz, 2H), 3.90 (s, 2H), 3.68 (s, 2H), 3.61 - 3.67 (m, 2H), 3.25-3.31 (m, 3H), 2.41-2.54 (m, 2H), 2.36 (s, 3H), 2.34 (s broad) , 2H).

EXAMPLE 63 5-. { 1- (3-methylphenyl) acetm-2,3-dihydro-1 H-indol-5-yl) -7- (1-methyl-4-piperidinyl) - 7 H -pyrrolor-2,3-cnpyrimidin-4-amine To a solution of 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (97 mg, 0.193 mmol) in DMF (3 mL) was added cesium carbonate (188 mg, 0.578 mmol). ) and then iodomethane (0.013 ml, 0.212 mmol). After 2 h the reaction was filtered and the filtrate was concentrated and then loaded onto a 10 g SNAP column. Elution with gradient of MeOH in DCM from 0 to 10% gave the 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methyl-4-piperidinopyrrolo [2,3-d] pyrimidin-4-amine (40 mg, 43.2% yield) as a white solid LC-MS (ES) m / z = 481, 4 [M + H] +.

EXAMPLE 64 5-. { 1-r (3-methylphenyl) acetin-2,3-dihydro-1½-indol-5-yl) thienor-2,3-c / 1-pyrimidin-4-amine mixture of 5-bromothieno [2,3-d] pyrimidin-4-amine (90 mg 0.391 mmol) and 1 - [(3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl- 1, 3,2-dioxaborolan-2-yl) -2,3-dthydro-1 H-indole (148 mg, 0.391 mmol) in 1,4-dioxane (6 mL) and saturated aqueous solution of NaHCO 3 (2 mL) it was degassed with N2 for 10 minutes. The adduct of PdCI2 (dppf) -CH2Cl2 (15.97 mg, 0.020 mmol) was added, and the reaction mixture was stirred overnight at 100 ° C in a sealed container. The reaction was cooled to room temperature and poured into water. The aqueous mixture was filtered, and the solid in the filter was purified by flash chromatography on S1O2 (gradient: from 100% hexanes to 100% EtOAc) to provide the desired product (19 mg) as a white solid. LC-MS (ES) m / z = 401, 3 [M + H] +. H-NMR (400 MHz, DMSO-de) d 2.31 (s, 3 H), 3.22 (t, J = 8.46 Hz, 2 H), 3.84 (s, 2 H), 4, 23 (t, J = 8.46 Hz, 2 H), 7.04-7.16 (m, 3 H), 7.20-7.29 (m, 2 H), 7.34 (s, 1 H), 7.42 (s, 1 H), 8, 17 (d, J = 8.34 Hz, 1 H), 8.34 (s, 1 H).

EXAMPLE 65 3-. { 1-rf3-fluoro-5-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl) furor3.2-clpyridin-4-amine A mixture of 3- (2,3-dihydro-1 H-indol-5-yl) furo [3,2-c] pyridin-4-amine (150 mg, 0.440 mmol), 3-fluoro-5-methylphenylacetic acid (78 mg, 0.464 mmol), HATU (184 mg, 0.484 mmol) and Hunig's base (0.31 mL, 1.775 mmol) in?,? - dimethylformamide (DMF) (3 mi) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 4 hours, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven ovght to give the 3-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (164 mg, 0.388 mmol, 88% yield) as a brown solid. LC / MS (ES) m / z = 402 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 2.32 (s, 3 H), 3.24 (t, J = 8.46 Hz, 2 H), 3.87 (s, 2 H), 4, 24 (t, J = 8.59 Hz, 2 H), 5.53 (s, 2 H), 6.90 - 7.00 (m, 4 H), 7.30 (d, J = 8.34 Hz, 1 H), 7.39 (s, 1 H), 7.86 (d, J = 5.81 Hz, 1 H), 7.92 (s, 1 H), 8.17 (d, J = 8.34 Hz, 1 H).

EXAMPLE 66 3- (1-r (3-chloro-5-fluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) furor3.2-clpyridin-4-amine A mixture of 3- (2,3-dihydro-1 H-indol-5-yl) furo [3,2-c] pyridin-4-amine (150 mg, 0.440 mmol), acid 3-Chloro-5-fluorophenylacetic acid (89 mg, 0.472 mmol), HATU (184 mg, 0.484 mmol) and Hunig's base (0.31 mL, 1.775 mmol) in?,? - Dimethylformamide (DMF) (3 mL) ) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 1 hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven ovght to give the 3-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (176 mg, 0.396 mmol, 90% yield) as a beige solid. LC / MS (ES) m / z = 422, 424 [M + H] +. 1 H NMR (400 MHz, D SO-d 6) d 3.27 (t, 2 H), 3.96 (s, 2 H), 4.26 (t, J = 8.46 Hz, 2 H), 5 , 53 (s, 2 H), 6.93 (d, J = 5.81 Hz, 1 H), 7.14 - 7.22 (m, 1 H), 7.27 (s, 1 H), 7.28-7.38 (m, 2 H), 7.40 (s, 1 H), 7.86 (d, J = 5.81 Hz, 1 H), 7.92 (s, 1 H) , 8.15 (d, J = 8.34 Hz, 1 H).

EXAMPLE 67 3- (1-r (2-fluoro-5-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl> furor3.2- clpyridin-4-amine A mixture of 3- (2,3-dihydro-1 H -indole-5-yl) furo [3,2-c] pyridin-4-amine (150 mg, 0.440 mmol), 2-fluoro-5 acid methylphenylacetic acid (78 mg, 0.464 mmol), HATU (185 mg, 0.487 mmol) and Hunig's base (0.31 mL, 1.775 mmol) in?,? - dimethylformamide (DMF) (3 mL) was stirred at room temperature. environment for 4 days. Water (10 mL) was added, the mixture was stirred for about 1 hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven ovght to give the 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (174 mg, 0.412 mmol, 94% yield) as a beige solid. LC / MS (ES) m / z = 402 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 2.29 (s, 3 H), 3.27 (t, J = 8.34 Hz, 2 H), 3.89 (s, 2 H), 4, 29 (t, J = 8.46 Hz, 2 H), 5.53 (s, 2 H), 6.93 (d, J = 6.06 Hz, 1 H), 7.03-7.18 ( m, 3 H), 7.30 (d, J = 8.08 Hz, 1 H), 7.40 (s, 1 H), 7.86 (d, J = 5.81 Hz, 1 H), 7.92 (s, 1 H), 8.13 (d, J = 8.08 Hz, 1 H).

EXAMPLE 68 1 - . 1 -methyl-3-. { 1-G (1-methyl-1 A / -pyrrol-2-yl) acet -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolor-3,4-onpyrimidin-4-amine Solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-amine (100 mg, 0.330 mmol), acid (1-methyl-1 H-pyrrol-2-yl) acetic acid (46 mg, 0.33 mmol), HATU (126 mg, 0.330 mmol), and DIEA (0.231 mL, 1. 321 mmol) was stirred at room temperature during one night. The LCMS analysis indicated good conversion, whereby the crude product was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried in the pump for 30 minutes. The crude product was adsorbed on silica and purified by flash chromatography (methanol in 0-10% DCM) to provide the -methyl-3-. { 1 - [(1-methyl-1 H-pyrrol-2-yl) acetyl] -2, 3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine (57.9 mg, 0. 149 mmol, 45.2% yield) as a white solid. LC-MS (ES) m / z = 388 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.25 (m, 2 H), 3.55 (s, 3 H), 3.86 - 3.90 (m, 2 H), 3.94 (s , 3 H), 4.21 - 4.32 (m, 2 H), 5.86 - 5.93 (m, 2 H), 6.66 - 6.71 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.49 - 7.53 (m, 1 H), 8, 13 - 8.22 (m, 1 H), 8.23 - 8.27 (m, 1 H). Note: NH are not observed in the NMR spectrum.

EXAMPLE 69 3- (1-R3-chloropheni!) Acetin-2,3-dihydro-1-indol-5-yl) furor3.2-c1pyridin-4-amine A mixture of 3- (2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (150 mg, 0.440 mmol), 3-Chlorophenylacetic acid (79 mg, 0.463 mmol), HATU (185 mg, 0.487 mmol) and Hunig's base (0.31 mL, 1.775 mmol) in N, N-dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 4 hours, and the precipitate was collected by vacuum filtration. It was purified by flash chromatography (Analogix, 24 g of S1O2, gradient of EtOAc in hexanes at 25% -100% over 30 minutes, then EtOAc for 10 minutes) to give 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (126 mg, 0.296 mmol, 67.4% yield) as an off-white solid. LC / MS (ES) m / z = 404, 406 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.25 (t, J = 8.34 Hz, 2 H), 3.93 (s, 2 H), 4.25 (t, J = 8.46 Hz) , 2 H), 5.54 (broad s, 2 H), 6.93 (d, J = 5.81 Hz, 1 H), 7.24 - 7.46 (m, 6 H), 7.86 (d, J = 5.81 Hz, 1 H), 7.92 (s, 1 H), 8.16 (d, J = 8.34 Hz, 1 H).

EXAMPLE 70 5- (1-r (2,3-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl> -7-methyl-7H-pyrrolor-2,3-c /] pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), (2,3-difluorophenyl) acetic acid (40.3 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. Hunig (0.163 mL, 0.936 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into water (100 ml) and a white solid formed. EtOAc (100 ml) was used to extract the product. The organic phase was separated from the aqueous phase, dried with MgSO 4, and evaporated to dryness to give an off white solid. The solid was treated with sonication in water (10 mL), then filtered and dried to provide the title compound as an off-white solid. It contained 1 eq. of DMF by NMR. H-NMR (400 MHz, DMSO-d6) d ppm 3.23-3.30 (m, 2 H), 3.73 (s, 3 H), 4.02 (s, 2 H), 4.30 ( t, J = 8.46 Hz, 2 H), 7, 17 - 7.24 (m, 3 H), 7.26 (s, 1 H), 7.33 (s, 2 H), 8.08 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 71 5-. { 1-r (2-fluoro-3-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl-7-methyl »- ^ pyrrolor2,3-cfypyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.6 mg, 0.234 mmol), (2-fluoro-3-methylphenyl) acetic acid (39.3 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig base (0.163 ml, 0.936 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide the title compound as an off-white solid. It had 0.7 eq. of DMF by NMR. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.25 (s, 3 H), 3.21 - 3.29 (m, 2 H), 3.73 (s, 3 H), 3.90 ( s, 2 H), 4.27 (t, J = 8.46 Hz, 2 H), 7.07 (d, J = 7.58 Hz, 1 H), 7.14 (s, 1 H), 7.21 (m, 2 H), 7.26 (s, 1 H), 7.32 (s, 1 H), 8.09 (d, J = 8.34 Hz, 1 H), 8, 14 (s, 1 H).

EXAMPLE 72 5-. { 1-r (3-fluoro-2-methylphenyl) acetin-2,3-dihydro-1 Hndol-5-yl) -7-methyl-7-pyrrolof2,3-c-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70.5 mg, 0.234 mmol), (3-fluoro-2-methylphenyl) acetic acid (39.3 mg, 0.234 mmol), HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig base (0.163 ml, 0.934 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide 5-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (96 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.14 (d, J = 1.52 Hz, 3 H), 3.21 - 3.29 (m, 2 H), 3.73 (s, 3 H), 3.95 (s, 2 H), 4.28 (t, J = 8.46 Hz, 2 H), 7.03-7.10 (m, 2 H), 7.17-7, 22 (m, 1 H), 7.24 (s, 1 H), 7.25 (s, 1 H), 7.32 (s, 1 H), 8, 10 (d, = 8.34 Hz, 1 H), 8, 14 (s, 1 H).

EXAMPLE 73 5- (1-r (2-fluoro-5-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl> -7-methyl-7H-pyrrolof2.3-cnp »rimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (71.6 mg, 0.237 mmol), (2-fluoro-5-methylphenyl) acetic acid (39.9 mg, 0.237 mmol), HATU (90 mg, 0.237 mmol) in DMF (2 ml) was added Hunig base (0.166 ml, 0.949 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide 5-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (85 mg) as an off-white solid. He had 0.8 eq of DMF based on the NMR analysis. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.29 (s, 3 H), 3.25 (t, J = 8.46 Hz, 2 H), 3.73 (s, 3 H), 3 , 87 (s, 2 H), 4.27 (t, J = 8.46 Hz, 2 H), 7.09 - 7.16 (m, 3 H), 7.22 (d, J = 8, 08 Hz, 1 H), 7.26 (s, 1 H), 7.32 (s, 1 H), 8.09 (d, = 8.34 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 74 3- (1-r (2-fluoro-3-methylphenyl) acetn-2,3-dihydro-1H-indol-5-yl-1-methyl-1H-pyrazolof3,4-c-pyrimidin-4-amine In a 20 ml vial with stopper, to 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pyrimidin-4-amine .2HCl (70 mg, 0.206 mmol), (2-fluoro-3-methylphenyl) acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base. (0.144 mL, 0.825 mmol). The mixture was stirred overnight. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the 3-. { 1 - [(2-fluoro-3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (71 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-cfe) d ppm 2.25 (d, J = 1.52 Hz, 3 H), 3.24-3.32 (m, 2 H), 3.92 (s, 2 H), 3.94 (s, 3 H), 4.30 (t, J = 8.46 Hz, 2 H), 7.04 - 7.1 1 (m, 1 H), 7.16 (s) , 1 H), 7.21 (s, 1 H), 7.44 (d, J = 8.34 Hz, 1 H), 7.53 (s, 1 H), 8, 16 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 75 3- (1-R (3-fluoro-2-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl> -1-methyl-1H-pyrazolor3,4-lpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3- • < dihydro-1 H-indol-5-yl) -1-methyl-1 H-pyrazolo [3,4-d ] pyrimidin-4-amine.2HCl (70 mg, 0.206 mmol), (3-fluoro-2-methylphenyl) acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 ml) ) Hunig's base (0.144 ml, 0.825 mmol) was added. The mixture was stirred overnight. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound (73 mg) as an off-white solid. 1 H NMR (400 MHz, DMSO-cfe) d ppm 2.15 (d, J = 1.52 Hz, 3 H), 3.24-3.31 (m, 2 H), 3.94 (s, 3 H), 3.97 (s, 2 H), 4.27 - 4.34 (m, 2 H), 7.04 - 7.11 (m, 2 H), 7.19 (d, J = 6 , 32 Hz, 1 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.53 (s, 1 H), 8.16 (d, J = 8.08 Hz, 1 H ), 8.25 (s, 1 H).

EXAMPLE 76 5- (1-r (2,55-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl> -7- (1-methyl-4-piperidinyl) -7H-pyrrolor-2,3-cnpyrimidin-4- amine At 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimid-4-amino (85 mg, 0.174 mmol) was added?,? -dimethylformamide (DMF) ( 2 ml) and cesium carbonate (170 mg, 0.522 mmol). Then iodomethane (0.014 ml, 0.226 mmol) was added to the mixture and the reaction was allowed to stir at room temperature overnight. The reaction was then filtered using the syringe filter and the filtrate was then diluted with water (20 mL) and then extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with brine, dried over MgSO4, filtered, concentrated and then loaded onto a 10 g Biotage SNAP column. Elution with gradient of MeOH in DCM from 0 to 10% over 30 min gave the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methy1-4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (16 mg, 0.032 mmol, 18.30% yield) as a white solid . LC / S (ES) m / z = 503.4 [M + H] +. H-NMR (400 MHz, DMSO-d6) d 8.13 (s, 1 H), 8.08 (d, J = 8.08 Hz, 1 H), 7.40 (s, 1 H), 7.36 (s, 1 H), 7.15-7, 30 (m, 4H), 4.56 (d, J = 3.54 Hz, 1 H), 4.29 (t, J = 8.46 Hz, 2H), 3.95 (s, 2H), 3 , 27 (t, J = 8.46 Hz, 2H), 2.93 (broad s, 2H), 2.27 (s, 3H), 2.04-2.28 (m, 4H), 1.85 -1, 93 (m, 2H). The NH is not observed.

EXAMPLE 77 5- (1-r (3-parlo-4-fluorophenyl) acetin-2,3-dihydro-1-f-indol-5-yl-7-methyl-7H-pyrrolof2,3-c / lpyrimidm-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- Amine.HCl (66 mg, 0.219 mmol), (3-chloro-4-fluorophenyl) acetic acid (41.2 mg, 0.219 mmol), HATU (83 mg, 0.219 mmol) in DMF (2 mL) was added. Hunig (0.153 ml, 0.875 mmol). The mixture was stirred at t.a. during one night. The LCMS analysis showed that the reaction was complete. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.22-3.28 (m, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4.24 ( t, J = 8.59 Hz, 2 H), 7.23 (d, J = 8.34 Hz, 1 H), 7.26 (s, 1 H), 7.29-7.34 (m, 2 H), 7.36-7.42 (m, 1 H), 7.53 (dd, J = 7.33, 2.02 Hz, 1 H), 8.12 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 78 5- (1-r (3-chloro-2-fluorophenyl) acetin-2,3-dihydro-1-tf-indo »-5-yl) -7-methyl-7H-pyrrolor-2, 3-cflpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- Amine.HCl (66 mg, 0.219 mmol), (3-chloro-2-fluorophenyl) acetic acid (41.2 mg, 0.219 mmol), HATU (83 mg, 0.219 mmol) in DMF (2 mL) was added. Hunig (0.153 ml, 0.875 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide the title compound as an off-white solid. He had 1 eq of DMF based on the NMR analysis. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.27-3.29 (m, 2 H), 3.74 (s, 3 H), 4.01 (s, 2 H), 4.26 - 4.33 (m, 2 H), 7.20 -7.27 (m, 3 H), 7.33 (m, 2 H), 7.52 (s, 1 H), 8.08 (d, J = 8.34 Hz, 1 H), 8, 15 (s, 1 H).

EXAMPLE 79 3-f1-r (3-Cioro-4-fluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl > -1-methyl-1-pyrazolor-3,4-dlpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 Hp -razolo [3,4-d] pyrimid N-4-amin.2HCl (64.6 mg, 0.190 mmol), (3-chloro-4-fluorophenyl) acetic acid (35.9 mg, 0.190 mmol), HATU (72.4 mg, 0.190 mmol) in DF (2 mL) was added Hunig's base (0.133 mL, 0.762 mmol). The mixture was stirred overnight. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.22-3.30 (m, 2 H), 3.94 (s, 5 H), 4.26 (t, J = 8.46 Hz, 2 H), 7.33 (dd, J = 4.93, 2.15 Hz, 1 H), 7.37-7.40 (m, 1 H), 7.41-7.47 (m, 1 H) ), 7.51-7.58 (m, 2 H), 8, 18 (d, J = 8.59 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 80 3-? -r (3-chloro-2-fluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl > -1-methyl-1 H- pyrazolor-3,4-o-pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H -pyrazolo [3,4-d] pinmidin-4 -arnine.2HCl (65.3 mg, 0.192 mmol), (3-chloro-2-fluorophenyl) acetic acid (36.3 mg, 0.192 mmol), HATU (73.2 mg, 0.192 mmol) in DMF (2 ml) ) Hunig's base (0.134 ml, 0.770 mmol) was added. The mixture was stirred overnight. The reaction was poured into water and a whitish solid formed. The solid was filtered to give the title compound as an off-white solid. He had 0.75 eq of DMF based on the NMR analysis. 1 H NMR (400 MHz, DMSO- / 6) d ppm 3.25-3.31 (m, 2 H), 3.94 (s, 3 H), 4.04 (s, 2 H), 4.32 (t, J = 8.46 Hz, 2 H), 7.20-7.26 (m, 1 H), 7.33 (d, J = 1.52 Hz, 1 H), 7.35 (s) , 1 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.50-7.57 (m, 2 H), 8.14 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 81 5- (1-r (2,3-dimethylphenyl) acetin-2,3-dihydro-1H-indol-5-yl> -7-methyl-7-pyrrolor-2,3- < flpirimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (66 mg, 0.219 mmol), (2,3-dimethylphenyl) acetic acid (35.9 mg, 0.219 mmol), HATU (83 mg, 0.219 mmol) in DMF (2 mL) was added Hunig's base ( 0. 153 mL, 0.875 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide the title compound (78 mg) as an off-white solid (78 mg). H NMR (400 MHz, DMSO-cfe) d ppm 2.12 (s, 3 H), 2.27 (s, 3 H), 3.20 - 3.27 (m, 2 H), 3.73 ( s, 3 H), 3.89 (s, 2 H), 4.26 (t, J = 8.46 Hz, 2 H), 7.02 (d, J = 6.82 Hz, 2 H), 7.05-7.09 (m, 1 H), 7.22 (d, J = 8.59 Hz, 1 H), 7.25 (s, 1 H), 7.32 (s, 1 H) , 8.1 (d, J = 8.08 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 82 l ^ l-methylethin-S-ll-nS-methylpheninacetin ^ .S-dihydro-IH-indol-S-yl ^ -IH-pyrazolor3,4-c / lpyrimidin-4-amine 3-vodo-1 H-pyrazolo [3,4-dlpyrimidin-4-amine] To a solution of 1 H-pyrazolo [3,4-d] pyrimidin-4-amine (1000 mg, 7.40 mmol) in?,? - dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature , NIS (1998 mg, 8.88 mmol) was added. The reaction mixture was stirred at 80 ° C for 5 h. The reaction was allowed to cool to room temperature. The mixture was concentrated, and NH 4 OH solution (20 mL) and EtOH (20 mL) were added. The precipitated white solid was filtered and dried to give 1.24 g of 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-amine. LC / MS (ES) m / z = 261, 9 [M + H] +. 3- I o- 1- (1-methylethyl) -1 H-pyrazoloyl 3,4-d] pyrimidin-4-amine To the 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (200 mg, 0.766 mmol) in?,? - dimethylformamide (DMF) (5 mL) cesium carbonate (300 mg) was added. , 0.919 mmol) followed by 2-iodopropane (0.080 ml, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80 ° C in a sealed container. The reaction was allowed to cool to room temperature. The mixture was poured into water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO 4), filtered and concentrated to provide 3-iodo-1- (1-methylethyl) -1 / - / - pyrazolo [3,4-d] pyrimidine. -4-amine (160 mg) as a white solid. LC / MS (ES) m / z = 340 [M + H] +. 1- (1-methylethyl) -3-. { 1- (3-methylphenyl) acetyl ^ 1 H-pyrazoloyl, 4-dlpyrimidin-4-amine A 25 ml pressure tube was charged with 3-iodo-1- (1-methylethyl) -1H-pyrazolo [3,4-c] pyrimidin-4-amine (70.9 mg, 0.234 mmol), 1- [ (3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (88 mg, 0.234 mmol ), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) -dichloromethane dichloride complex (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane ( 8 mi) and water (2 mi). The reaction was heated at 120 ° C for 40 min in a microwave reactor. The reaction was cooled to room temperature, the mixture was transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and the black greasy solid remaining in the tube, a total of 100 ml of EtOAc was added to the mixture . The EtOAc solution was evaporated to dryness, and redissolved in CH 2 Cl 2 / MeOH (8 ml / 2 ml). Purify by flash column with 25-100% EtOAc / hexane, then 0-10% MeOH / EtOAc, Si SF15-24 g, to give a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the compound of the title in the form of a brown solid. LC / MS (ES) m / z = 427.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.48 (d, J = 6.82 Hz, 6 H), 2.31 (s, 3 H), 3.22-3.27 (m, 2) H), 3.85 (s, 2 H), 4.23 (t, J = 8.34 Hz, 2 H), 5.02 - 5.09 (m, 1 H), 7.07-7, 14 (m, 3 H), 7.20-7.27 (m, 1 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.51 (s, 1 H), 8 , 20 (d, J = 8.08 Hz, 1 H), 8.22 (s, 1 H).

EXAMPLE 83 2- (4-amino-3- < 1 -r (3-methylphenyl) acetin-2,3-dihydro-1 H-indol-5-ylM H-pyrazolor3,4-lpyrimidin-1-yl) ethanol 2- (4-amino-3-iodo-1 H-pyrrazolo [3,4-dlpyrimidin-1-yl] ethanol) To the 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (200 mg, 0.766 mmol) in?,? - dimethylformamide (DMF) (5 mL) cesium carbonate (300 mg) was added. , 0.919 mmol) followed by 2-bromoethanol (0.057 ml, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80 ° C in a sealed container. The reaction was allowed to cool to room temperature. The mixture was concentrated and treated with water (~10 mL). The resulting aqueous mixture was sonicated, and then filtered. The solid in the filter was washed with water (2 x 10 mL) to give the 2- (4-amino-3-iodo-1 / - / - pyrazolo [3,4-d] pyrimid) 1-l) ethanol (128 mg) as a white solid after drying. LC / MS (ES) m / z = 306.0 [M + H] +. 2- (4-amino-3 1-r (3-methylphenyl) acetill-2,3-dM ^ pyrazolo [3, 4-dlpyrimidin- 1 -iDetanol 2- (4-Amino-3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-1-l) ethanol (63.8 mg, 0.209 mmol) was charged in a 25 ml pressure tube. 1 - [(3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole ( 79 mg, 0.209 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride complex (II) -dichloromethane (8.54 mg, 0.011 mmol) and sodium bicarbonate (35.1 mg, 0.418 mmol) followed by dioxane (8 ml) and water (2 ml). The reaction was heated at 120 ° C for 40 min in a microwave apparatus. The reaction was cooled to room temperature, the mixture transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and greasy black solid remaining in the tube (100 ml of EtOAc was added in total to the mixture). ). The EtOAc solution was concentrated to dryness, and redissolved in CH2Cl2 / MeOH (8 mL / 2 mL). Purify by flash column with 25-100% EtOAc / hexane, then 0-10% MeOH / EtOAc, Si SF15-24 g, to give a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC / MS (ES) m / z = 429.4 [M + Hf. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.31 (s, 3 H), 3.24 (s, 2 H), 3.80 - 3.88 (m, 4 H), 4.19 - 4.27 (m, 2 H), 4.37 (t, J = 5.81 Hz, 2 H), 4.89 (t, J = 5.68 Hz, 1 H), 7.07-7, 14 (m, 3 H), 7.20-7.28 (m, 1 H), 7.45 (d, J = 8.08 Hz, 1 H), 7.51 (s, 1 H), 8 , 21 (d, J = 8.34 Hz, 1 H), 8.23 (s, 1 H).

EXAMPLE 84 5- (1-r (3,5-dimethylphenyl) acetun-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3- pyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (66 mg, 0.129 mmol), (3,5-dimethylphenyl) acetic acid (35.9 mg, 0.219 mmol), HATU (83 mg, 0.219 mmol) in DMF (2 mL) was added Hunig's base ( 0.153 mL, 0.875 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a white solid formed. The solid was filtered and dried to provide the title compound as an off-white solid. LC / MS (ES) m / z = 412.4 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 2.26 (s, 6 H), 3.20 (t, J = 8.46 Hz, 2 H), 3.73 (s, 3 H), 3 , 77 (s, 2 H), 4, 19 (t, J = 8.46 Hz, 2 H), 6.87 -6.94 (m, 3 H), 7.20-7.27 (m, 1 H), 7.25 (s, 1 H), 7.29 (s, 1 H), 8.14 (d, J = 8.34 Hz, 1 H), 8, 14 (s, 1 H) .

EXAMPLE 85 5- (1-r (2,5-difluorophenyl) acetill-213-dihydro-1 H -indol-5-yl) -7- (4-piperidinyl) -7H-pyrrolor-2,3-cflpyrimidin-4-amine 4- (5-bromo-4-chloro-7H-pyrroloyl, 3-dlDiimidin-7-iD-1-piperidinecarboxylate 1,1-dimethylethyl) To a solution of 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (214 mg, 0.921 mmol), 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (556 mg, , 76 mmol) and triphenylphosphine (483 mg, 1, 841 mmol) in non-tear tetra break (THF) (10 mL) was added dropwise DEAD (0.291 mL, 1.841 mmol). The solution was allowed to stir at room temperature. After 2 h the reaction was concentrated and purified by chromatography on silica gel to provide 4- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1 -1,1-dimethylethylpiperidinecarboxylate (330 mg, 86% yield) as a white solid. 4- (4-amino-5-bromo-7H-pyrrolo [2,3-dlpyrimidin-7-iQ-1-piperidinecarboxH, 1,1-dimethylethyl ester] To 4-1-dimethylethyl 4- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate (313 mg, 0.753 mmol) was added ammonium hydroxide ( 2 ml, 51.4 mmol) and 1,4-dioxane (1 ml) in a 5 ml microwave vial and heated in a microwave for 20 min at 100 ° C. After 35 min in total the reaction was complete. The reaction was concentrated to give the 4- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate 1,1-dimethylethyl ester (336 mg), which it was used without further purification. 4- (4-amino-5- { 1 -i (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-ill-7H-pyrrolof2, 3-dlpihmidin- - / 7) - 1-1-dimethylethyl-1-piperidinecarboxylate The 4- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (138 mg, 0.348 mmol) and 1 - [( 2,5-difluorophenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (167 mg , 0.418 mmol) were dissolved in 1,4-dioxane (5 ml) and then saturated NaHCO 3 solution (2 ml) was added. The mixture was then bubbled with N2 gas for 10 min and then Pd (Ph3P) (40.2 mg, 0.035 mmol) was added and then the mixture was bubbled for an additional 5 minutes. Then, the reaction was capped and heated at 100 ° C for 4 h. The mixture was allowed to cool and then diluted with water (10 ml) and then extracted with EtOAc (3x20 ml). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to isolate an amber oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with ne and eluting with a gradient of MeOH in DCM from 0 to 10% for 30 minutes to give 4- (4-amino-5-. [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.] - 7 H -pyrrolo [2,3-d] pyrimidin-7-yl) -1-piperidinecarboxylate of 1, -dimethylethyl (160 mg, 0.272 mmol, 78% yield) as an amber oil. LC / MS (ES) m / z = 589.6 [M + Hf. 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} - 7- (4- Diperidinyl) - 7H-oirrolof2.3-dloirimidin-4-amine Al 4- (4-amino-5- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-H-indol-5-yl.}. -7H-pyrrolo [2,3 -d] pyrimidin-7-yl) -1-piperidine carboxylate of, 1-dimethylethyl (180 mg, 0.306 mmol) was added 4M HCl (4 mL, 16.00 mmol) in dioxane. The reaction was allowed to stir at room temperature overnight. The reaction was concentrated, then diluted with diethyl ether and filtered to isolate the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (140 mg, 0.249 mmol, 82% yield) as the dihydrochloride salt, as a light yellow solid. LC / MS (ES) m / z = 489.0 [M + H] +. 1 H NMR (400 MHz, methanol-d 4) d 8.39 (s, 1 H), 8.24 (d, J = 8.34 Hz, 1 H), 7.61 (s, 1 H), 7, 44 (s, 1 H), 7.32-7.37 (m, 1 H), 7.04-7.20 (m, 3H), 5.08-5, 18 (m, 1 H), 4 , 36 (t, J = 8.46 Hz, 2H), 3.99 (s, 2H), 3.68 (s, 3H), 3.65 (d, J = 13.89 Hz, 2H), 3 , 36-3.40 (m, 2H), 2.41-2.53 (m, 2H), 2.37 (d, 2H).

EXAMPLE 86 1 - . 1-ethyl-3- (1-r (3-methylfentl) acetin-2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolor 3,4- c-pyrimidin-4-amine 1-ethyl-3-vodo-1H-pyrazolo [3,4-dlpyrimidin-4-amine] To the 3-iodo-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (200 mg, 0.766 mmol) in?,? - dimethylformamide (DMF) (5 mL) cesium carbonate (300 mg) was added. , 0.919 mmol) followed by iodoethane (0.065 ml, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80 ° C in a sealed container. The reaction was allowed to cool to room temperature. The mixture was poured into water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO 4), filtered and concentrated. Flash chromatography on S1O2 (gradient: from 100% CH2CI2 to CH2Cl2: CH30H: NH4OH 90: 10: 1) yielded 1-ethyl-3-iodo-1 H-pyrazolo [3,4-c /] pyrimidin -4-amine (15 mg) as a white solid. 1 - . 1-ethyl-3- (1-y (3-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4-dlpyrimidin-4-amine] A 25 ml microwave pressure tube was charged with 1-ethyl-3-iodo-1 / - / - pyrazolo [3,4-d] pyrimidin-4-amine (105 mg, 0.363 mmol), 1 - [( 3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (137 mg, 0.363 mmol) , 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) -dichloromethane dichloride complex (14.83 mg, 0.018 mmol), and sodium bicarbonate (61.0 mg, 0.726 mmol) followed by dioxane (4). mi) and water (1 mi). The reaction was sealed and heated at 120 ° C for 40 minutes in a microwave reactor. The reaction was cooled to room temperature, the mixture was transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and greasy black solid remaining in the tube (50 ml of EtOAc was added in total to the mixture). ). The EtOAc solution was evaporated to dryness, and redissolved in CH2Cl2 / MeOH (4 mL / 1 mL). Purify by flash column with 25-100% EtOAc / hexane, then 0-10% MeOH / EtOAc (Analogix Si SF cartridge 5-24 g), to give a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC / MS (ES) m / z = 4 3.3 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 1.41 (t, = 7.20 Hz, 3 H), 2.31 (s, 3 H), 3.21 - 3.29 (m, 2 H) ), 3.85 (s, 2 H), 4.23 (t, J = 8.46 Hz, 2 H), 4.32-4.40 (m, 2 H), 7.07-7, 14 (m, 3 H), 7.21-7.28 (m, 1 H), 7.44-7.46 (m, 1 H), 7.51 (s, 1 H), 8.21 (d) , J = 8.34 Hz, 1 H), 8.24 (s, 1 H).

EXAMPLE 87 3- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl> -7-methylfuror3,2-clpyridin-4-amine A mixture of 3-. { 1 - [(2,5-difluorophenol) acetl] -2,3-dihydro-1 H -indole-5-yl} -7-iodofuro [3,2-c] pyridin-4-amine (253 mg, 0.476 mmol), trimethylboroxin (0.07 ml, 0.502 mmol), adduct of PdCl2 (dppf) -CH2Cl2 (19 mg, 0.023 mmol) and K2CO3 (197 mg, 1.425 mmol) in 1,4-dioxane (2.5 ml) and water (0.5 ml) was degassed with nitrogen for 10 minutes. The vial was then capped and the mixture was stirred at 100 ° C for 15 h. The LCMS analysis showed a mixture of starting material (20%), desired product (36%), and deionized byproduct (40%). The mixture was filtered, rinsing with EtOAc (approximately 35 ml). The filtrate was washed with water (1 * 25 ml) and brine (1 x 25 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The recovery was quite small (<200 mg), whereby the aqueous phases were combined and extracted with methylene chloride (3 * 25 ml), and the extracts were dried (Na2SO4), filtered, combined with the EtOAc layer of the pretreatment and concentrated in vacuo (total mass> 200 mg). The residue was purified by reverse phase HPLC (Gilson, C18, gradient of CH3CN in water with 0.1% TFA, from 25% to 45%, 8 minutes). The fractions With product, they were concentrated, taken up in MeOH, and passed through a PL-HC03 cartridge. The filtrate was concentrated in vacuo, triturated with diethyl ether, and dried in the vacuum oven overnight. The NMR analysis indicated that the compound was still a salt of TFA, and presented an impurity. The solid was taken up in DCM (5 ml) and poured into saturated aqueous solution of NaHCO 3 (5 ml). The organic layer was collected and the aqueous layer was extracted with methylene chloride (2 x 5 mL). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was further purified by flash chromatography (Analogix, 12 g of Si02, gradient of EtOAc in hexanes 50% -00% over 7.5 minutes, EtOAc for 2.5 minutes, then gradient of MeOH in EtOAc 0-5% over 10 minutes) to give the 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methylfuro [3,2-c] pyridin-4-amine (29 mg, 0.066 mmol, 13.79% yield) as a white solid. LC / MS (ES) m / z = 420 [M + Hf. 1 H NMR (400 MHz, DMSO-d 6) d 2.30 (s, 3 H), 3.28 (t, J = 8.21 Hz, 2 H), 3.96 (s, 2 H), 4, 30 (t, J = 8.46 Hz, 2 H), 5.31 (s, 2 H), 7.14-7.34 (m, 4 H), 7.41 (s, 1 H), 7 , 69 (s, 1 H), 7.95 (s, 1 H), 8, 12 (d, J = 8.34 Hz, 1 H).

EXAMPLE 88 3-f 1 -r (2,5-difluorophenyl) acetin-2,3-dihydro-1 fí-indole-5- ?? - (1-methyl-ethyl) -1 H-pyrazolor-3,4-c-pyrimidin-4-amine A 25 ml pressure tube was charged with 3-iodo-1- (1-methylethyl) -1H-pyrrazolo [3,4-d] pnnmdin-4-amino (70.9 mg , 0.234 mmol), 1 - [(2,5-difluorophenol) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-d-oxaborolan-2-yl) -2 3-D-Hydro-1 H-indole (93 mg, 0.234 mmol), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride complex (II) -dichloromethane (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane (4 mL) and water (1 mL). The reaction was heated at 120 ° C for 40 min in a microwave reactor. LC S analysis showed incomplete conversion. The reaction was heated in a microwave at 120 ° C for an additional 1 hour. The reaction was cooled to room temperature, the mixture transferred to a 100 ml Erlenmeyer flask, rinsed with EtOAc, the water layer and greasy black solid remaining in the tube (100 ml of EtOAc was added in total to the mixture). ). The EtOAc solution was evaporated to dryness, and redissolved in CH2Cl2 / MeOH (8 ml / 2 ml). Purified by flash column with 25-100% EtOAc / hexane, then 0-10% eOH / EtOAc, Analogix Si SF15-24 g, to provide a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC / MS (ES) m / z = 449.4 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 1.49 (d, J = 6.82 Hz, 6 H), 3.27-3.33 (m, 2 H), 3.97 (s, 2 H), 4.31 (t, J = 8.46 Hz, 2 H), 5.06 (t, J = 6.82 Hz, 1 H), 7, 18 - 7.21 (m, 1 H) , 7.22-7.27 (m, 2 H), 7.44 (d, J = 8.08 Hz, 1 H), 7.54 (s, 1 H), 8.15 (d, J = 8.34 Hz, 1 H), 8.23 (s, 1 H).

EXAMPLE 89 5-1'-rf3,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl > -7-methyl-7H-pyrrolor2,3- / lpyrimidin-4-amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrazolo [2,3-d] pyrimidin-4-amine.2HCl (150 mg, 0.443 mmol) , (3,5-difluorophenyl) acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The LCMS analysis indicated partial conversion, with a mixture of starting material, the desired product and bisacylated material, whereby the reaction mixture was poured into water (10 ml) and a precipitate formed. He The precipitate was collected by filtration and the residue was washed with water (10 ml), and dried in the pump for 1 hour. The beige solid was adsorbed on silica and purified by flash chromatography (methanol in 0-10% DCM, 12 g column) to give a pale yellow solid showing the presence of bisacylated material. The product was adsorbed on silica and purified by flash chromatography (100% EtOAc-MeOH in 10% EtOAc, then MeOH in 10% DCM, 24 g column) to provide 5-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (92 mg, 49.5% yield) as a white solid. LC-MS (ES) m / z = 420 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.21 -3.28 (m, 2 H), 3.74 (s, 3 H), 3.95 (s, 2 H), 4.24 (t , J = 8.34 Hz, 2 H), 6.04 (broad s, 2 H), 7.06 (d, J = 6.57 Hz, 2 H), 7, 14 (t, J = 9, 60 Hz, 1 H), 7.21 - 7.29 (m, 2 H), 7.33 (s, 1 H), 8.07 - 8.21 (m, 2 H).

EXAMPLE 90 7-methyl-5- (1-r (2,3,5-trifluorophenyl) acetyl-2-dihydro-1H-indol-5-ii-7H-pyrrolo ^ S-cflpyrimidin -amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (150 mg, 0.443 mmol) , (2,3,5-trifluorophenyl) acetic acid, HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The LCMS analysis (62-A1-ON) indicated the partial conversion, with a mixture of starting material, the desired product and bisacylated material, whereby the reaction mixture was poured into water (10 ml) and a precipitate. The precipitate was collected by filtration and the residue was washed with water (10 ml), and dried on the pump for 1 hour. The beige solid was adsorbed on silica and purified by flash chromatography (methanol in 0-10% DCM, 12 g column) to give a pale yellow solid showing the presence of bisacylated material. The product was adsorbed on silica and purified by flash chromatography (100% EtOAc-MeOH in 10% EtOAc, then MeOH in 10% DCM, 12 g column) to provide 7-methyl-5. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-arnine (102 mg, 52.6% yield) as a white solid. LC-MS (ES) m / z = 438 [M + H] +. 1 H-NMR (DMSO-d 6,400 MHz): d 3.28 (t, J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 4.04 (s, 2 H), 4 , 29 (t, J = 8.5 Hz, 2 H), 6.08 (broad s, 2 H), 7, 10 -7, 17 (m, 1 H), 7.20 - 7.28 (m , 2 H), 7.34 (s, 1 H), 7.42 - 7.53 (m, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 8.15 ( s, 1 H).

EXAMPLE 91 5-. { 1-r (3,5-dichlorophenacetin-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolof213- / lpyrimidin-4-amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine 2HCl (250 mg, 0.739 mmol), 5- (2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (250 mg, 0.739 mmol), HATU (281 mg, 0,739 mmol), DIEA (0.516 mL, 2.96 mmol) was stirred at room temperature overnight. The LCMS analysis indicated a good conversion, whereby the reaction mixture was poured into water (10 ml), after which a precipitate formed. The precipitate was filtered and washed with water (10 ml) and dried in the pump for 1 hour. The residual pale green solid was adsorbed on silica and purified by flash chromatography (from 100% EtOAc to MeOH in 10% EtOAc, 12 g column) to give the 5-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (285 mg, 85% yield) as a white solid. LC-MS (ES) m / z = 452, 454 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.25 (t, J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 3.95 (s, 2 H), 4, 24 (t, J = 8.5 Hz, 2 H), 6.25 - 5.87 (broad s, 2 H), 7.28 - 7.20 (m, 2 H), 7.33 (s, 1 H), 7.39 (d, J = 1.8 Hz, 2 H), 7.52 (d, J = 1.8 Hz, 1 H), 8.1 1 (d, J = 8.1) Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 92 7- (3-azetidinyl) -5- (1-r (3-methylphenyl) acet-2,3-dihydro-1H-indol-5-yl> -7H-pyrrolor-2,3-dlpyrimidin-4-amine 3- (5-bromo-4-chloro-7H-dihydrolof 2,3-dlDirimidin-7-yl) -1-azetidinecarboxylate 1,1-dimethylethyl ester To a solution of 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (400 mg, 1.721 mmol), 1,1-dimethylethyl 3-hydroxy-1-azetidinecarboxylate (894 mg , 5.16 mmol) and triphenylphosphine (903 mg, 3.44 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (545 μ ?, 3.44 mmol). The dissolution let stir at room temperature. After 1 h 10% of the reaction product was observed and the reaction was heated to 60 ° C. After 1 h, 80% of the desired product was observed. An additional 100 mg of 5-bromo-4-chloro-1 H-pyrrolo [2,3-d] pyrimidine was added and heating continued. The reaction was concentrated, then loaded onto a 25 g SNAP column with gradient EtOAc in hexane from 0 to 35% over 30 minutes to give 3- (5-bromo-4-chloro-7H-pyrrolo [ 2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylic acid 1,1-dimethylethyl ester (624 mg, 94% yield) as a white solid. LC-MS (ES) m / z = 386.9, 389, 1 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.69 (s, 1 H), 8.38 (s, 1 H), 5.53-5.62 (m, 1 H), 4.33 (d) , J = 8.34 Hz, 4H), 1.43 (s, 9H). 3- (4-amino-5-bromo-7H-Dyrrolor-2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate 1,1-dimethylethyl ester To the 1,1-dimethylethyl 3- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate (690 mg, 1.780 mmol) was added hydroxide ammonium (69.3 μ ?, 1.780 mmol) in a 20 ml microwave vial. The capped vial was heated at 100 ° C for a total of 2 h in the microwave reactor. The reaction was checked every 0.5 h. Only 15% of the desired product was observed. The reaction was filtered. To the solid, NH 4 OH (4 ml) was added in a 20 ml microwave vial and the vial was heated in an oil bath at 90 ° C for 24 h. 80% product was observed in the reaction. Additional 1 ml of NH 4 OH was added and heating was continued overnight. The The reaction was filtered and washed to give the 3- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate 1,1-dimethylethyl ester (538 mg) with 78% purity. LC-MS (ES) m / z = 368.2, 370.2 [M + H] +. 3- (4-amino-5- { 1 -r (3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl-7H-pyrrolofc.S-dipyrimidine-J-ill- 1, 1-dimethylethyl l-azetidinecarboxylate To the 1,1-dimethylethyl 3- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate (200 mg, 0.543 mmol) and 1 - [( 3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (246 mg, 0.652 mmol) dissolved in 14-dioxane (4 mL) was added saturated solution of NaHCO 3 (2 mL). The mixture was then bubbled with N 2 gas for 10 minutes, then Pd (Ph 3 P) 4 (62.8 mg, 0.054 mmol) was added and then it was bubbled for an additional 5 minutes. The reaction was then capped and heated at 100 ° C overnight. The mixture was allowed to cool, then diluted with water (10 mL) and then extracted with EtOAc (3x20 mL). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with hexane using a gradient of 0 to 10% MeOH in DCM for 30 minutes to isolate 3- (4-amino-5- { 1 - [( 3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} - 7 H -pyrrolo [2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate of 1, 1-dimethylethyl (197 mg, 0.366 mmol, 67.3% yield) as an amber solid. LC-MS (ES) m / z = 539.3 [M + H] +. 1 H NMR (400 MHz, DMSO- d6) d 8, 1 1 - 8, 18 (m, 2H), 7.60 (s, 1 H), 7.37 (s, 1 H), 7.28 (d, J = 8.34 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.06-7.15 (m, 3H), 5.76 (s, 1 H), 5.46-5.56 (m , 1 H), 4.33 (d, J = 8.08 Hz, 4H), 4.21 (t, J = 8.46 Hz, 2H), 3.93 (s, 1 H), 3.83 (s, 2H), 3.22 (t, J = 8.21 Hz, 2H), 2.31 (s, 3H), 1.43 (s, 9H). 7- (3-azetidinyl) -5-. { 1- (3-methylphenyl) acetyl-2,3-dihydro-1 H-indol-5-iD-7H-pyrrolo [2,3-d] pyrimidin-4-amine To 3- (4-amino-5- { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} - 7 H -pyrrolo [2, 3-d] pyrimid-7-yl) -1-azetidinacarboxylate 1,1-dimethylethyl ester (198 mg, 0.368 mmol) was added 4N HCl in dioxane (4 ml, 16.00 mmol). The starting material remains oily outside the solution and even heating at 50 ° C during the night there was no conversion. After the reaction was concentrated and DCM (4 mL) and TFA (2 mL) were added. The starting material was dissolved in the solution and after 1 h the reaction was complete. The reaction was concentrated, then diluted with EtOAc (20 mL) and then washed with saturated Na2CC > 3. A precipitate appeared in the solution and the mixture was extracted with a mixture of 20% isopropyl alcohol in DCM (3x50 ml). The organic extracts were combined and dried over Na 2 SO 4, filtered and concentrated to give a yellow oil. The oil was dissolved in 1 ml of DMF and then loaded onto a 10 g Biotage column with DCM in DCM: MeOH: 1 NH4OH 95: 5: 1 mixture, from 0 to 100% for 15 min, then DCM mixture : MeOH: 1 95: 5: 1 NH4OH at 100% for 15 minutes to isolate 7- (3-azetidinyl) -5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (103 mg, 0.235 mmol, 63.9% yield) as a clear oil. LC-MS (ES) m / z = 439.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.15 (d, J = 8.34 Hz, 1 H), 8.13 (s, 1 H), 7.62 (s, 1 H), 7, 36 (s, 1 H), 7.25-7.30 (m, 1 H), 7.23 (d, J = 7.33 Hz, 1 H), 7.06-7.14 (m, 3H) ), 6.09 (broad s, 2H), 5.50 (t, J = 7.45 Hz, 1 H), 4.22 (t, J = 8.34 Hz, 2H), 3.91 - 3 , 96 (m, 2H), 3.78 - 3.85 (m, 4H), 3.18 - 3.25 (m, 2H), 2.31 (s, 3H).

EXAMPLE 93 5- (1 (4-fluorophenynacetin-2,3-dihydro-1H-indol-5-yl-7-methyl-7H-pyrrolor-2,3-cnpyrimidin-4-amine 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine. HCl (70 mg, 0.232 mmol), (4-fluorophenyl) acetic acid (37.5 mg, 0.244 mmol), and HATU (93 mg, 0.244 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 402.3 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.23 (t, J = 8.34 Hz, 2 H), 3.73 (s, 3 H), 3.88 (s, 2 H), 4.23 (t, J = 8.46 Hz) , 2 H), 7, 15 - 7.20 (m, 2 H), 7.21 - 7.26 (m, 2 H), 7.30 - 7.37 (m, 3 H), 8.13 (d, J = 8.34 Hz, 1 H), 8, 15 (s, 1 H).

EXAMPLE 94 7-methyl-5- (1-r (4-methylphenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7H-pyrrolor-2,3-dlpyrimidin-4-amine In a 20 ml vial with stopper, to a solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70 mg, 0.232 mmol), (4-methylphenyl) acetic acid (36.6 mg, 0.244 mmol), and HATU (93 mg, 0.244 mmol) in DMF (2 mL) was added Hunig's base (0%). 162 mL, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 598.3 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 2.30 (s, 3 H), 3.20 (t, J = 8.34 Hz, 2 H), 3.73 (s, 3 H), 3 , 82 (s, 2 H), 4, 15-4.23 (m, 2 H), 7, 15 (d, J = 8.08 Hz, 2 H), 7.20 (d, J = 8, 08 Hz, 3 H), 7.25 (s, 1 H), 7.30 (s, 1 H), 8.14 (s, 2 H).

EXAMPLE 95 5- (1-r (3-chloro-2 ^ -difluorophenyl) acet'n-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-cnpyrimidin-4-amine In a 20 ml vial with stopper, to a solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrol. min-4-amino-HCl (70 mg, 0.232 mmol), (3-chloro-2,4-difluorophenyl) acetic acid (47.9 mg, 0.232 mmol), and HATU (93 mg, 0.244 mmol) ) in DMF (2 ml) was added Hunig's base (0.162 ml, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 454.3 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 3.22 - 3.29 (m, 2 H), 3.74 (s, 3 H), 4.01 (s, 2 H), 4.26 - 4.33 (m, 2 H), 7.21-7.28 (m, 1 H), 7.26 (s, 1 H), 7.29-7.36 (m, 2 H), 7, 40 (dd, J = 8.34, 6.32 Hz, 1 H), 8.08 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 96 5- (1- (3-Fluoro-5- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1H-indol-5-ih-7- methyl-7H-pyrrolor-2,3-clpyrimidin-4-amine To a suspension of 5- (2,3-dihydro-H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine 2HCl (1.80 mg, 5.32 mmol, 1 equiv) and HATU (2.23 mg, 5.85 mmol, 1.1 equiv) in 18 mL of DMF was added DIEA (2.97 mL, 17.03 mmol, 3%). , 2 equiv) in one portion. The mixture was transformed into a clear, pale brown solution, and cooled in an ice bath. To this stirred solution was added [3-fluoro-5- (trifluoromethyl) phenyl] acetic acid (1.18, 5.32 mmol, 1 equiv) in portions as a solid over a period of 1 h. After the addition of the acid was complete, the cooling bath was removed. After 30 min, the mixture became a milky texture. After 1, 5 h more, the mixture was poured into 200 ml of ice water to give a suspension, which was filtered. The filter cake was washed with water and diethyl ether, and then dried with a laboratory vacuum system at room temperature for 18 hours. This material was dissolved in MeOH in 10% DCM, and was absorbed in 3 dry-charge silica gel cartridges (in approximately equal portions). Purification was done on an Analogix silica gel cartridge SF40-80 g using elution with gradient of 1% A to A in 60% CHCl3 (A was a mixture of CHCl3 / MeOH / NH4OH 3200/800/80). The desired product eluted in A at 23-28%. The collected fractions were combined and concentrated in vacuo to provide the product as a white residue. The impure fractions that came out in the front (A at 21-22%) were combined and the residue (the LCMS analysis showed the presence of a non-polar impurity) was dissolved in MeOH in 10% DCM and absorbed in a cartridge of dry loading. Purification was done on an Analogix silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc at 75% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 59-75%. The combined fractions were concentrated in vacuo to provide additional product, which was combined with the above pure sample and dissolved in 70 ml of MeOH in 10% DCM, followed by filtration. The filtrate was concentrated in vacuo. The residue was taken up in 40 ml of MeOH in 10% DCM. The mixture was concentrated in vacuo to about 0 ml. The suspension was diluted with 20 ml of MTBE, and then concentrated in vacuo to half the volume. The mixture was diluted again with 20 ml of MTBE. The resulting suspension was filtered. The filter cake was washed with MTBE (3x 15 mL). The solids were then dried under vacuum at 65 ° C for 48 h to provide 5- (1 - { [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (2.026 g) as white solids. LC-MS (ES) m / z = 470 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.26 (t, J = 8.3 Hz, 2 H), 3.73 (s, 3 H), 4.07 (s, 2 H), 4 , 27 (t, J = 8.5 Hz, 2 H), 5.91 - 6.26 (broad s, 1.4 H), 7.23 (d, = 8.3 Hz, 1 H), 7 , 26 (s, 1 H), 7.33 (s, 1 H), 7.51 (d, J = 9.6 Hz, 1 H), 7.56 - 7.64 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 8.15 (s, 1 H) ).

EXAMPLE 97 7-R (methyloxy) metin-5- (1-r (3-methylphenyl) acetin-2,3-dihydro-1H-indol.5-n pyrrolor2.3-dlpyrimtdin-4-amine 5-bromo-7 - [(methyloxy) methyl] -7H-pyrrolof2, 3-d] pyrimidin-4-amine 5-Bromo-4-chloro-7 - [(methyloxy) methyl] -7H-pyrrolo [2,3-d] pyrimidine (200 mg, 0.723 mmol) was transferred to a 5 ml microwave vial and then Ammonium hydroxide (1.5 ml, 38.5 mmol) was added. The mixture was heated in a microwave reactor at 100 ° C for 30 minutes. The solid was isolated by filtration and dried to give 5-bromo-7 - [(methyloxy) methyl] -7H-pyrrolo [2,3- d] pyrimidin-4-amino (132 mg, 71.0% yield) as a solid White. LC-MS (ES) m / z = 257.0, 259.0 [M + H] +. 1 H-NMR (400 MHz, DMSO-d 6) d 8.14 (s, 1 H), 7.56 (s, 1 H), 6.81 (broad s, 2H), 5.43 (s, 2H), 3.21 (s, 3H). 7 (methyloxy) methyl-5-. { 1-f (3-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-yl} - 7H-pyrrolo [2, 3-d1-pyrimidin-4-amine To 5-bromo-7 - [(methoxyl) methyl] -7H-pyrrolo [2,3-d] p, n, idn-4-amine (65 mg, 0.253 mmol) and 1 - [(3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (114 mg, 0.303 mmol) dissolved in 1,4-dioxane (2 mL) was added saturated solution of NaHCO 3 (1 mL). The mixture was then bubbled with N2 gas for 10 minutes, then Pd (Ph3P) 4 (29.2 mg, 0.025 mmol) was added and then it was bubbled for an additional 5 minutes. The reaction was then capped and heated at 100 ° C overnight. The mixture was cooled, then diluted with water (10 mL) and extracted with EtOAc (3x20 mL). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil. The oil was then purified on a 10 g Biotage SNAP column conditioned with hexane using a gradient of MeOH in DCM from 0 to 10% for 30 minutes to isolate 7 - [(methyloxy) methyl] -5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (36 mg) as a white solid. LC-MS (ES) m / z = 428.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.17 (s, 1 H), 8.15 (d, J = 8.34 Hz, 1 H), 7.37 (s, 1 H), 7, 32-7.35 (m, 1 H), 7.24 (dd, J = 7.33, 14.65 Hz, 2H), 7.06-7.15 (m, 3H), 6.15 (s) width, 2H), 5.50 (s, 2H), 4.21 (s, 2H), 3.83 (s, 2H), 3.25 (s, 3H), 3.19 - 3.25 (m , 2H), 2.31 (s, 3H).

EXAMPLE 98 7-methyl-5- (1 (1-methyl-1H-pyrrol-2-yl) acetin-2,3-dihydro-1H-indol-5-yl) -7H-pyrrolor-2,3-d-pyrimidine-4- amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (250 mg, 0.739 mmol) , 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrirnidin-4-amine.2HCl (250 mg, 0.739 mmol), HATU (281 mg, 0.739 mmol), DIEA (0.516 mL, 2.96 mmol) was stirred at room temperature overnight. The reaction mixture was poured into 20 ml of water and stirred for 30 min. The gray precipitate was filtered, washed with water (10 ml) and dried for one hour in the pump. The residue was adsorbed on silica and purified by flash chromatography (MeOH in 0-10% DCM, 24 g column) to give 7-methyl-5. { 1 - [(1-methyl-1H-pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (128 mg, 44.8% yield) as a white solid. LC-MS (ES) m / z = 387 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.23 (t, J = 8.34 Hz, 2 H), 3.54 (s, 3 H), 3.73 (s, 3 H), 3, 86 (s, 2 H), 4.25 (t, J = 8.59 Hz, 2 H), 5.84 - 5.94 (m, 2 H), 5.94 - 6.32 (m, 2) H), 6.68 (t, J = 2.15 Hz, 1 H), 7.14 - 7.29 (m, 2 H), 7.31 (s, 1 H), 8.08 - 8, 20 (m, 2 H). An additional crop of material was obtained from the crystals obtained in the filtrate after standing overnight. The liquid was filtered and the residue was washed with water and dried in the pump to give a second crop of 7-methyl-5-. { 1 - [(1-methyl-1 H-pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (65 mg, 22.76% yield) as a beige solid.

EXAMPLE 99 5- (1-r (2,5-difluorophenyl) acetin-2,3-diM ^ pyrrolor2,3-t / lpyrimidin-4-amine To 5-bromo-7- (1-methylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.392 mmol) and 1 - [(2,5-difluorophenyl) acetyl] - 5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -2,3-dihydro-H-indole (188 mg, 0.470 mmol) was added 1,4-dioxane ( 2 ml) and saturated NaHCO 3 solution (1 ml) in a 5 ml vial with airtight seal. The mixture was then bubbled with N2 for 10 minutes, then Pd (Ph3P) 4 (45.3 mg, 0.039 mmol) was added and bubbled for an additional 5 minutes. Then it was capped and heated at 100 ° C overnight. Then the reaction was checked by LCMS analysis and 10% of the bromide starting material remained. 50 mg of the boronic ester was added, and the reaction was capped and heated at 100 ° C for an additional 5 h. The The reaction was diluted with water (5 ml) and then extracted with EtOAc (3x10 ml). The organic extracts were combined, washed with brine and dried over MgSO4, filtered and concentrated. Then the residual oil was diluted with DMSO (3 mL) and then purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7 , 3 minutes (47 ml / min, ACN / 28% H2O, 0.1% TFA to ACN / 53% H2O, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated aHCO3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO, filtered and concentrated. The product was transferred to a 40 ml vial with MeCN, then water was added and lyophilized to isolate the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (76 mgl, 43.3% yield) as a white solid. LC-MS (ES) m / z = 448.4 [M + Hf. 1 H NMR (400 MHz, DMSO-d 6) d 8.13 (s, 1 H), 8.09 (d, J = 8.08 Hz, 1 H), 7.42 (s, 1 H), 7, 36 (s, 1 H), 7.14 - 7.30 (m, 4H), 6.08 (broad s, 2H), 4.97 (quin, J = 6.76 Hz, 1 H), 4, 29 (t, J = 8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J = 8.46 Hz, 2H), 1.46 (d, = 6.82 Hz , 6H).

EXAMPLE 100 5-f1-r (5-chloro-2-fluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-cnpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (70 mg, 0.232 mmol), (5-chloro-2-fluorophenyl) acetic acid (44.2 mg, 0.234 mmol) and HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added. Hunig (0.162 ml, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and an off-white solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 436.4 [M + Hf. NMR nH (400 MHz, DMSO-d6) d ppm 3.22-3.30 (m, 2 H), 3.74 (s, 3 H), 3.96 (s, 2 H), 4.25- 4.32 (m, 2 H), 7.21-7.28 (m, 2 H), 7.30 (s, 1 H), 7.33 (s, 1 H), 7.39-7, 44 (m, 1 H), 7.47 (dd, J = 6.32, 2.78 Hz, 1 H), 8.08 (d, J = 8.34 Hz, 1 H), 8.15 ( s, 1 H).

EXAMPLE 101 5- (1-r (2,5-difluorophenyl) acetn-2,3-dihydro-1 / y-indol-5-yl) -7-r2- (4-morpholinyl) etin-7H-pyrrolor 2,3 -c lpyrimidin-4-amine 5-bromo-4-chloro-7- [2- (4-morpholinyl) etyl-7H-pyrrolof2.3-d1-pyrimicline To 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyrididine (200 mg, 0.860 mmol), 2- (4-morpholinyl) ethanol (0.316 mL, 2.58 mmol ) and triphenylphosphine (451 mg, 1.721 mmol) was added tetrahydrofuran (THF) (5 mL). Then, DEAD reaction (0.222 ml, 1.721 mmol) was added dropwise. The solution was then allowed to stir overnight at room temperature. The reaction was then concentrated and diluted with water (10 mL) and then extracted with EtOAc (3x10 mL). The organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated. The yellow crude residue was then loaded onto a 25 g Biotage SNAP column and purified with 0 to 8% MeOH in DCM gradient over 30 minutes to give 5-bromo-4-chloro-7- [2 - (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidine (245 mg, 82% yield) as a light yellow solid. LC-MS (ES) m / z = 347.2 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d 8.67 (s, 1 H), 8.05 (s, 1 H), 4.39 (t, J = 6.19 Hz, 2H), 3.48 (t , J = 4.29 Hz, 4H), 2.71 (t, J = 6.32 Hz, 2H), 2.42 (broad s, 4H). 5-bromo- 7- [2- (4-morpholinyl) etyl-7H-pyrrolo [2,3-dlpyrimidin-4-amine at 5-bromo-4-chloro-7- [2- (4-morpholinyl) ethyl) ] -7H-pyrrolo [2,3-d] pyrimidine (240 mg, 0.694 mmol) in a 5 ml vial with airtight seal was added ammonium hydroxide (1.5 ml, 38.5 mmol). The reaction vial was capped and heated at 100 ° C overnight. The reaction was cooled and a solid formed. The solid was isolated by filtration and the solid was washed with NH 4 OH. The solid was air-dried to isolate the desired product, 5-bromo-7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (154 mg, 68 mg). , 0% yield) in the form of a whitish solid. LC-MS (ES) m / z = 326.1 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8, 10 (s, 1 H), 7.47 (s, 1 H), 6.69 (broad s, 2H), 4.22 (t, J = 6 , 44 Hz, 2H), 3.52 (t, J = 4.42 Hz, 4H), 2.65 (t, J = 6.44 Hz, 2H), 2.41 (d, = 4.04 Hz , 4H). 5-Y1-γ (2,5-difluorophenyl) acetyl-2,3-dihydro-1 H-indol-5-yl} - 7-Í2-Í4-morpholine Detill-7H-pyrrolo [2,3-dlpyrimidin-4-amine To 5-bromo-7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.307 mmol), 1 - [(2,5- difluorophenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (159 mg, 0.399 mmol) in a 5 ml vial with a tight seal was added 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (1 ml). After the mixture was bubbled with N2 gas for 10 minutes and then Pd (Ph3P) 4 (35.4 mg, 0.031 mmol) was added. The mixture was again bubbled with N 2 gas for 5 minutes, then capped and the reaction was heated at 100 ° C overnight. The reaction was diluted with water (3 mL) and then extracted with EtOAc (3x5 mL). Then the organic extracts were combined and washed with brine, dried over MgSO, filtered and concentrated. The residue was then dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minute experiment (47 ml / min, ACN / 7% H2O, 0.1% TFA at 32% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO 3 solution was added and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. It was then transferred to a 40 ml vial with MeCN, then water was added and lyophilized to isolate the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-H-indol-5-yl} -7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (76 mg, 47.8% yield) as a white solid. LC-MS (ES) m / z = 519.5 [M + H] +.

EXAMPLE 102 5- (1-r (2,4-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-cflpyrimidin-4-amine In a 20 ml vial with stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.HCl (71 mg, 0.235 mmol), (2,4-difluorophenyl) acetic acid (40.9 mg, 0.238 mmol), and HATU (90 mg, 0.238 mmol) in DMF (2 mL) was added Hunig's base. (0.164 mL, 0.941 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 420.4 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.26 (t, J = 8.34 Hz, 2 H), 3.73 (s, 3 H), 3.92 (s, 2 H), 4 , 28 (t, J = 8.46 Hz, 2 H), 7.08-7.09 (m, 1 H), 7.20-7.28 (m, 3 H), 7.33 (s, 1 H), 7.40 (d, J = 7.58 Hz, 1 H), 8.08 (d, J = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 103 5- (1-r (3,4-difluorophenyl) acetun-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrroloyl-2,3-Cflpyrimidin-4-amine In a 20 ml vial with a stopper, to the solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.HCl (70 mg, 0.232 mmol), (3,4-difluorophenyl) acetic acid (39.9 mg, 0.232 mmol), and HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol ). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 420.4 [M + H] +. 1 H NMR (400 MHz, DMSO-c 6) d ppm 3.21 - 3.28 (m, 2 H), 3.73 (s, 3 H), 3.91 (s, 2 H), 4.24 (t, = 8.21 Hz, 2 H), 7, 15 (s, 1 H), 7.21 - 7.28 (m, 2 H), 7.32 (s, 1 H), 7.34 - 7.42 (m, 2 H), 8.12 -8.15 (m, 2 H).

EXAMPLE 104 r2- (4-amino-3- (1-r (215-difluorophenyl) acetyl-2-dihydro-1H-indol-5- il) furof3,2-c1pyridin-7-yl) phenylmethyl etincarbamate (3- { 1-f (2,5-difluorophenyl) acetill-2, 3-dihydro-1H-indol-5-yl.} - 7- bisd, 1 -dimethylethyl vodofuroí3,2-clDiridin-4-yl) imidodicarbonato) A mixture of 3-. { 1 - [(2,5-D-fluoro-phenyl) -acetyl] -2,3-dihydro-1 H-indol- 5-l} -7-iodofuro [3,2-c] pyridin-4-amino (1.652 g, 2.488 mmol), Boc20 (4.06 mL, 17.48 mmol), triethylamine (2.42 mL, 17.46 mmol), and DMAP (0.017 g, 0.139 mmol) in dichloromethane (DCM) (25 ml) was stirred at room temperature under nitrogen for 17 hours. The LCMS analysis indicated only approximately 50% conversion, so another portion of Boc20 (4.06 mL, 17.48 mmol), and stirring was continued for 3 days (end of week). Then, the reaction mixture was concentrated in vacuo and the residue it was purified by flash chromatography (Analogix, 90 g of S1O2, gradient of EtOAc in hexanes at 5% -30% over 50 minutes) to give the (3- { [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-iodofuro [3,2-c] pyrid'm il) bis (1,1-dimethylethyl) imidodicarbonate (749 mg, 1.024 mmol, 41.2% yield) as a yellow foam. LC / MS (ES) m / z = 732 [M + H] +. (3- {1-G (2,5-difluorophenyl) acetill-2,3-dihydro-1H-indol-5-yl} - 7? 2 - (([(phenylmethyl) oxylcarbonyl}. amino) ethylfluoro [3,2-clpyr ^ ^ of bis (1,1-dimethylethyl) A mixture of (3- {1 - [(2,5-d? -fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl}. -7-iodophide [3, 2-c] pyridin-4-yl) bis (1,1-dimethylethyl) mdicadocarbonate (302 mg, 0.413 mmol), benzyl-N- [2- (trifluoroborane) ethyl) ] potassium carbamate (90 mg, 0.316 mmol), palladium acetate (II) (9 mg, 0.040 mmol), RuPhos (38 mg, 0.081 mmol), and cesium carbonate (403 mg, 1.237 mmol) in toluene (3 mL) and water (1 mL) was degassed with nitrogen for 10 minutes. Then the 25 ml vial was capped and stirred vigorously at 95 ° C for 16 hours. The LCMS analysis showed the complete consumption of the starting material and a good conversion in the desired product, together with a peak of 23% corresponding to the deionized by-product. It was cooled, diluted with ethyl acetate (15 mL), and washed with a mixture of water (5 mL) and saturated aqueous solution of NaHCO3 (10 mL). The aqueous phase was back extracted with EtOAc (15 mL), and the combined organic phases were washed with brine (1 * 15 mL), dried (a2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g of SiO2, gradient of EtOAc in hexanes at 5% -70% over 55 minutes) to give the. { 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- ( { [(Phenylmethyl) oxy] carbonyl}. Amino) ethyl] furo [3,2-c] pyridin-4-yl} bis (1,1-dimethylethyl) imidodicarbonate (149 mg, 0.190 mmol, 46.1% yield) as an off-white foam. LC / MS (ES) m / z = 783.9 [M + H] +. r2- (4-amino-3-. {-1 (2,5-difluorophenyl) acetill-2,3-dihydro-1H- ^ il.}. furor3,2-clpyridine-7-yl) phenylmethyl ethenylcarbamate A mix of . { 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- ( { [(Phenylmethyl) oxy] carbonyl}. Amino) ethyl] furo [3,2-c] pyridin-4-yl} bis (, 1-dimethylethyl) imidodicarbonate (149 mg, 0.190 mmol) and 4.0 M HCl in dioxane (2.0 ml, 8.00 mmol) was stirred at room temperature under nitrogen atmosphere for 4 h. Then the crude reaction mixture was concentrated in vacuo and azeotropically distilled once with acetonitrile. The residue was taken up in DCM and passed through a MP PL-HC03 MP resin cartridge, rinsing with more DCM. The filtrate was then concentrated in vacuo to give the free base of [2- (4-amino-3. {1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indole 5-yl.} Phenylmethyl [3,2-c] pyridin-7-yl) ethyl] carbamate (105 mg, 0.162 mmol, 85% yield) as an off-white foam (calculated purity of 90%) . LC / MS (ES) m / z = 583.6 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d 2.86 (t, J = 7.07 Hz, 2 H), 3.22-3.34 (m, 4 H), 3.96 (s, 2 H) ), 4.31 (t, J = 8.34 Hz, 2 H), 5.02 (s, 2 H), 5.38 (s, 2 H), 7.14-7.44 (m, 12) H), 7.68 (s, 1 H), 7.93 (s, 1 H), 8.12 (d, J = 8.34 Hz, 1 H).

EXAMPLE 105 pyrrolor2,3- / 1-pyrimidin-4-amine 5-bromo-7- (3-methylbutyl) -7H-pyrroloyl-2,3-dlpyrimidin-4-am To 5-bromo-4-chloro-7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrididine (210 mg, 0.694 mmol) in a 5 ml vial with an airtight seal, ammonium hydroxide (1.5 ml, 38.5 mmol) was added. The mixture was then capped and heated at room temperature overnight. The reaction was cooled and a precipitate formed. The solid was isolated by filtration and air dried to isolate 5-bromo-7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (191 mg, 0.675 mmol, 97% of yield) in the form of a light brown solid. For 50-A1: LC / S (ES) m / z = 283.2, 285.2 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8, 10 (s, 1 H), 7.48 (s, 1 H), 6.70 (broad s, 2H), 4, 12 (t, J = 7 , 20 Hz, 2H), 1, 64 (q, = 6.99 Hz, 2H), 1.44 (ddd, J = 6.69, 6.82, 13.26 Hz, 1 H), 0.90 (d, J = 6.57 Hz, 6H). 1 - . 1 -1 (2,5-difluorophenyl) acetill-5- (4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-H) -2, 3-dihydro-1 H-indole In a sealed tube, 5-bromo-1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indole (3.5 g, 9.94 mmol), bis (pinacolato) ) diboro (3.03 g, 11.93 mmol) and potassium acetate (2.93 g, 29.8 mmol) was added 1,4-dioxane (15 mL) and the mixture was degassed with N2 for 10 minutes. The adduct PdCl2 (dppf) -CH2Cl2 (0.406 g, 0.497 mmol) was added and the reaction mixture was stirred for 48 hours at 100 ° C. The mixture was cooled to room temperature. Ethyl acetate (300 ml) was poured into the mixture, stirred, and then filtered. The filtrate was poured into a separating funnel. It was washed with brine, dried (MgSO 4), filtered and concentrated. Purification by Analogix silica Si90, gradient of 0-40% EtOAc / hexane provided 1 - [(2,5-difluorophenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3.2 -dioxaborolan-2-yl) -2,3-dihydro-1 H-indole as a white solid (2.01 g). LC-MS (ES) m / z = 400.3 [M + H] +. 5-. { 1- (2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl) -7- (3-methylbutyl) -7H-pyrrolof2.3-dlpyrimidin-4-amine To 5-bromo-7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (13 mg, 0.399 mmol) and 1 - [(2,5-difluorophenyl) acetyl] - 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (207 mg, 0.519 mmol) in a 5 ml vial with Hermetically sealed 1, 4-dioxane (2 ml) and saturated NaHCO3 solution (1 ml) were added. The mixture was then bubbled with N 2 gas for 10 minutes. minutes and then Pd (Ph3P) 4 (46.1 mg, 0.040 mmol) was added. The mixture was again bubbled with N 2 gas for 5 minutes, then capped and the reaction was heated at 100 ° C overnight. The reaction was diluted with water (3 ml) and then extracted with EtOAc (3x mi). The organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The resulting amber oil was dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7 , 3 minutes (47 ml / min, 30% ACN / H20, 0.1% TFA to 55% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO 3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. It was then transferred to a 40 ml vial with MeCN, then water was added and lyophilized to give the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (58 mg, 30.6% yield) as a white solid. For 50-A1: LC / MS (ES) m / z = 476.5 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d 8.14 (s, 1 H), 8.08 (d, J = 8.34 Hz, 1 H), 7.35 (s, 1 H), 7, 33 (s, 1 H), 7.15-7.30 (m, 4H), 6.06 (broad s, 2H), 4.29 (t, J = 8.34 Hz, 2H), 4.18 (t, J = 7.20 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J = 8.46 Hz, 2H), 1.69 (q, J = 7.07 Hz , 2H), 1, 44-1,66 (m, 1 H), 0.93 (d, J = 6.57 Hz, 6H).

EXAMPLE 106 5- (1-rf2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7-r2- (dimethylamino) etin-7H-pyrrolor-2,3-cnpyrimidin-4-amine 2 - (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-iDetillimethylamine To a solution of 5-bromo-4-chloro-1 H-pyrrolo [2,3-d] pyrimidine (200 mg, 0.860 mmol), 2- (dimethylamino) ethanol (230 mg, 2.58 mmol) and triphenylphosphine ( 451 mg, 1.721 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (0.222 mL, 1.721 mmol). The solution was allowed to stir at room temperature. After 2 h the reaction was concentrated, then loaded onto a 25 g Biotage SNAP column and eluted with gradient eOH in DCM from 0 to 8% over 30 minutes to give the [2- (5-bromine -4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] dimethylamine (175 mg, 67.0% yield) as a white solid. LC / MS (ES) m / z = 303, 1, 305.1 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.67 (s, 1 H), 8.04 (s, H), 4.36 (t, J = 6.19 Hz, 2H), 2.67 ( t, J = 6.19 Hz, 2H), 2, 16 (s, 6H). 5-Bromo-7- [2- (dimethylamino) etH-7H-pyrrolo [2,3-d] pyrimidin-4-amine [2 (5-Bromo-4-chloro-7H-pyrrolo [2,3-d] pyridin-7-yl) ethyl] dimethylamine (175 mg, 0.576 mmol) was added ammonium hydroxide (22.45 μ ?, 0.576 mmol) in a 5 ml vial with airtight seal. Then the vial was capped and heated at 100 ° C overnight. The reaction was cooled to room temperature and concentrated to a light brown oil of 5-bromo-7- [2- (dimethylamino) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-. amine (190 mg, 0.669 mmol, 116% yield), which was used without further purification. LC / MS (ES) m / z = 284.1 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.14 (s, 1 H), 7.53 (s, 1 H), 6.82 (broad s, 2H), 4.48 (t, J = 6) , 32 Hz, 2H), 3.41 (broad s, 2H), 2.71 (s, 6H). 5-. { 1-F (2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} - 7-12- (dimethylamino) etyl-7H-pyrrolo [2,3-d] pyrimidine-4-amine To 5-bromo-7- [2- (dimethylamino) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (100 mg, 0.352 mmol), 1 - [(2,5-difluorophenyl)] acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (183 mg, 0.457 mmol) in a vial of 5 ml with a tight seal were added 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (1 ml). The mixture was then bubbled with N 2 gas for 10 minutes and then Pd (Ph 3 P) (40.7 mg, 0.035 mmol) was added. The mixture was again bubbled with N 2 gas for 5 minutes, then capped and the reaction was heated at 100 ° C overnight. The reaction dilute with water (3 ml) and then extract with EtOAc (3x mi). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The resulting amber oil was dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7 , 3 minutes (47 ml / min, 7% ACN / H20, 0.1% TFA to 37% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed in combination with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. It was then transferred to a 40 ml vial with MeCN, then water was added and lyophilized to give the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- (dimethylamino) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (35 mg LC / MS (ES) m / z = 477.5 [M + H] + 1 H NMR (400 MHz, DMSO-d 6) d 8.14 (s, H), 8.09 (d, J = 8.08 Hz, 1 H), 7.33 (s, 2 H), 7.15. - 7.30 (m, 4H), 6.06 (broad s, 2H), 4.24 - 4.33 (m, 4H), 3.95 (s, 2H), 3.24 - 3.30 ( m, 2H), 2.72 (broad s, 2H), 2.24 (broad s, 6H).

EXAMPLE 107 5-. { 1-r (6-chloro-2-pyridinyl) acetn-2,3-dihydro-1H-indol-5-yl > -7-methyl-7H-pyrrolof2,3-cnpyrimidin-4-amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrazolo [2, 3-d] pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (6-chloro-2-pyridinyl) acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310) mi, 1.774 mmol) was stirred at room temperature overnight. The resulting suspension was poured into water (10 ml) and stirred for 30 min. The resulting precipitate was collected by filtration, and the residue was washed with water (10 ml), and dried in the pump for about 1 hour. The solid residue was dissolved in acetone and adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to provide 5-. { 1 - [(6-chloro-2-pindinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pi d] pyrimidin-4-amine (99.8 mg, 53.7% yield) as a beige solid. LC-MS (ES) m / z = 419 [M + H] +. 1 H NMR (400 Hz, DMSO-de) d 3.25 (t, J = 8.34 Hz, 2 H), 3.74 (s, 3 H), 4.08 (s, 2 H), 4, 27 (t, J = 8.46 Hz, 2 H), 5.92 -6.22 (m, 2 H), 7.20-7.28 (m, 2 H), 7.33 (s, 1 H), 7.38-7.46 (m, 2 H), 7.87 (t, J = 7.83 Hz, 1 H), 8.10 (d, J = 8.34 Hz, 1 H) , 8, 15 (s, 1 H).

EXAMPLE 108 3- (1-r (3-Chloro-2,4-difluorophenyl) acetin-2,3-dihydro-1 H -indol-5-ylVl-methyl-1H-pyrazolor-3,4-cflpyrimidin-4-amine In a 20 ml vial with stopper, to a solution of 3- (2,3-dihydro-1 H-indol-5-yl) -1-methyl-1 Hp -razolo [3,4- d] pyrimidin-4-amine.HCl (70 mg, 0.231 mmol), (3-chloro-2,4-d.fluorophenyl) acetic acid (47.8 mg, 0.231 mmol), and HATU (88 mg, 0.231 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.925 mmol). The mixture was stirred overnight. The reaction was poured into water (100 ml) and a whitish solid formed. The solid was filtered, washed with water (10 ml) and dried to give the title compound as an off-white solid. LC-MS (ES) m / z = 455.4 [M + H] +. H NMR (400 MHz, DMSO-cfe) d ppm 3.24-3.31 (m, 2 H), 3.94 (s, 3 H), 4.03 (s, 2 H), 4.32 ( t, = 8.46 Hz, 2 H), 7.30-7.36 (m, 1 H), 7.39-7.46 (m, 2 H), 7.54 (s, 1 H), 8.14 (d, J = 8.34 Hz, 1 H), 8.25 (s, 1 H).

EXAMPLE 109 7- (2-aminoethyl) -3-n-r (2,5-difluorophenyl) acetyl-2,3-dihydro-1 H-indol-5-yl) furof3,2-c1pyridin-4-amine A suspension of [2- (4-amino-3- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H -indol-5-yl.} Furo [3, Phenylmethyl 2-c] pyridin-7-yl) ethyl] carbamate (91 mg, 0.156 mmol) and Pd / C (10% by weight, based on dry%), moist (approximately 50% water), Degussa type E101 NE / W (27 mg, 0.013 mmol) in ethanol (1 ml) and tetrahydrofuran (THF) (5 ml) was stirred under hydrogen atmosphere for 3 hours. The LCMS analysis showed no conversion and it appeared that the starting material was not very soluble in the reaction mixture. Some?,? - dimethylformamide (DMF) (2 mL) was added along with another portion of Pd / C (10% by weight, based on% dry), wet (approximately 50% water), Degussa type E101 NE / W (65 mg, 0.031 mmol), and the mixture was stirred under a hydrogen atmosphere for a further 19 hours. The LCMS analysis showed a mixture of product and a by-product. The mixture was filtered and the filtrate was concentrated in vacuo. An attempt was made to convert the by-product into the desired product by collecting the mixture in MeOH (approximately 10 ml), adding 2 M HCl (approximately 1 ml), and stirring at room temperature for 5 hours. No reaction was observed so it was heated at 50 ° C for another 16 hours. The HPLC analysis still showed no conversion, so the mixture was concentrated in vacuo. The residue was taken up in MeOH (1.5 mL) and purified by reverse phase HPLC (Gilson, C18, gradient of CH3CN in water with 0.1% TFA, from 20% to 27%, 8 minutes). The product fractions were concentrated in vacuo and azeotropically distilled with acetonitrile 3 times. Then the residue was taken up in DCM and passed through a resin cartridge MP PL-HC03 Varian, rinsing with more DCM. The filtrate was then concentrated in vacuo and dried in the vacuum oven overnight to give the free base of 7- (2-amino-ethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pi din-4-amine (18 mg, 24.41% yield) as a white solid. LC / MS (ES) m / z = 449 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 1.53 (broad s, 2 H), 2.72-2.79 (m, 2 H), 2.79-2.86 (m, 2 H), 3.28 (t, J = 8.34 Hz, 2 H), 3.96 (s, 2 H), 4.30 (t, J = 8.59 Hz, 2 H), 5.33 (s, 2 H), 7.14-7.33 (m, 4 H), 7.41 (s, 1 H), 7.69 (s, 1 H), 7.93 (s, 1 H), 8, 12 (d, J = 8.34 Hz, 1 H).

EXAMPLE 110 4-amino-3- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl> furor3.2 clpyridine-7-carbonitrile (7-cyano-3- { 1 -1 (2, 5-difluorophenyl) acetyl-2,3-dihydro-1 H-indol-5-H) furof3,2-clDirin-4-ii) bisd, 1-dimethylethyl imidodicarbonate) A mixture of (3- { 1 - [(2, 5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-iodofuro [3,2-c] pyridin-4-yl) imidodicarbonate of bis (1,1-d-methylethyl) (391 mg, 0.534 mmol), zinc (II) cyanide (83 mg, 0.707 mg) mmol), and tetrakis (triphenylphosphine) palladium (0) (30 mg, 0.026 mmol) in?,? - dimethylformamide (DMF) (4 ml) was degassed with nitrogen for 10 minutes. The vial was then capped and stirred at 120 ° C in the microwave reactor for 30 minutes. The crude reaction mixture was combined with the crude reaction mixture of an identical small-scale test reaction, diluted with EtOAc (25 ml), washed with half-saturated aqueous NaHCO 3 solution (2? 25 ml), dried ( Na2SO4), filtered and concentrated in vacuo to give an orange oil (331 mg). The LCMS analysis indicated a mixture of (7-cyano-3- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} Furo [ 3,2-c] pyridin-4-yl) imidodicarbonate of bis (1,1-dimethylethyl) and the product without Boc (approximately 3: 2). The mixture was used without further purification. 4-amino-3-. { 1-F (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl} furo [3, 2-clpridine-7-carbonitryl A mixture of (7-cyano-3- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.} Furo [3,2-c ] bis (1,1-dimethylethyl) pyridin-4-yl) (359 mg, 3: 2 mixture with the no-Boc described above) and 4.0 M HCl in dioxane (3.0 ml, 12 ml). , Mmol) was stirred at room temperature under nitrogen for 14 h. The mixture was concentrated in vacuo and taken up in EtOAc (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (1x50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g of S1O2, gradient of EtOAc in hexanes at 15% -85% over 52 minutes) to give 4-amino-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridine-7-carbonitrile (1 18 mg, 45.7% yield) as a white solid. LC / MS (ES) m / z = 431 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3,28 (t, 2 H), 3.97 (s, 2 H), 4.30 (t, J = 8.46 Hz, 2 H), 6, 57 (broad s, 2 H), 7.14-7.33 (m, 4 H), 7.40 (s, 1 H), 8.09 - 8.17 (m, 2 H), 8.38 (s, 1 H).

EXAMPLE 111 5- (1-r (3,5-dimethyl-1H-pyrazol-1-yl) acetyl-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-lpyrimidin- 4-amine To a mixture of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amino dihydrochloride (175 mg, 0.517 mmol) and (3,5-dimethyl-1 H-pyrazol-1-yl) acetic acid (80 mg, 0.517 mmol) in N, N-dimethylformamide (DMF) (3 mL) was added dropwise DIPEA (0.271 mL, 1.552 mmol). The mixture was cooled in an ice bath and then T3P (1-propanophosphonic acid cyclic anhydride) was added dropwise, 50% in ethyl acetate (~ 1.68 M) (0.370 ml, 0.621 mmol). After stirring 30 minutes, the ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with water (~5 mL) and basified to pH 7-8 with 0.5 M NaOH. Methanol was added to give a clear solution. This solution was loaded onto a C18 SF25-55g Analogix reversed-phase cartridge and the product was purified by eluting with a gradient of 30-95% methanol-water. The combined pure fractions containing the product were evaporated and azeotropically distilled with acetonitrile and then benzene to give a solid which was triturated with acetonitrile (~4 mL), filtered and washed with acetonitrile to give the 5-. { 1 - [(3,5-dimethyl-H-pyrazol-1-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (90 mg, 41.2% yield) as a white solid after drying in vacuo. LCMS (ES) m / z = 402.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.15 (s, 1 H), 8.07 (d, J = 8, 1 Hz, 1 H), 7.34 (s, 1 H), 7 , 20-7.29 (m, 2 H), 6.08 (br.s, 2 H), 5.86 (s, 1 H), 5.09 (s, 2 H), 4.26 (t , J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 3.27 (t, J = Q, 3 Hz, 2 H), 2.17 (8.3 H), 2 , 10 (s, 3 H).

EXAMPLE 112 5-r4-fluoro-1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-in-7-methyl-7H-pyrrolor-2,3-dlpyrimidin-4-amine 4-fluoro-2, 3-dihydro-1 H-indole To a stirred solution of 4-fluoro-1 H-indole (950 mg, 7.03 mmol) in acetic acid (20 mL) at 12 ° C under nitrogen was added sodium cyanoborohydride (1458 mg, 23.20 mmol) in portions. The reaction was stirred at 12 ° C for 2 hours and at room temperature overnight. The reaction was treated by pouring it into sodium hydroxide (10 N). The aqueous layer was extracted with diethyl ether (3 x 100 mL), and the combined organic extracts were dried over sodium sulfate. The LCMS analysis at this point indicated the presence of product and some acylated product, together with some acylated starting material. The crude product was dissolved in THF (10 mL) and treated with NaOH (6 N)., 2 ml), then stirred at t.a. for 2 h. The reaction was stirred overnight, but no change in the LCMS was observed, whereby the organic layer was removed and the aqueous layer was extracted with diethyl ether (2 x 0 mL), the combined organic extracts were dried over sodium sulfate. The dried solution was filtered and concentrated, and the residue was purified by flash chromatography (0-25% EtOAc in hexanes, 24 g silica gel column) to give 4-fluoro-2,3-dihydro-1 H -indole (510 mg, 3.72 mmol, 52.9% yield) as a colorless oil. LC-MS (ES) m / z = 138 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 2.94 (t, J = 8.59 Hz, 2 H), 3.48 (t, J = 8.59 Hz, 2 H), 5.79 (s) width, 1 H), 6.23-6.35 (m, 2 H), 6.87-6.99 (m, 1 H). 4-Fluoro-2,3-dihydro-1 H-indole-1-carboxylate, 1,1-dimethylethyl A solution of 4-fluoro-2,3-dihydro-H-indole (500 mg, 3.65 mmol), Boc20 (0.846 mL, 3.65 mmol), DIEA (1.273 mL, 7.29 mmol), DMAP (44.5 mg, 0.365 mmol) was stirred at room temperature overnight. The reaction mixture was poured into 0.1 N HCl (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the 4-fluoro-2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (0.866 g, 100% yield ) in the form of a colorless oil. LC-MS (ES) m / z = 182 [M + H- tBuf. 1 H NMR (400 MHz, DMSO-d 6) d 1.51 (s, 9 H), 3.08 (t, J = 8.72 Hz, 2 H), 3.97 (t, J = 8.72 Hz , 2 H), 6.77 (t, J = 8.72 Hz, 1 H), 7, 1 1 - 7.26 (m, 1 H), 7.27 -7.66 (m, 1 H) . 1, 1-dimethylethyl 5-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate To a solution of 1,1-dimethylethyl 4-fluoro-2,3-dihydro-1 H-indole-1-carboxylate (0.866 g, 3.65 mmol) in dichloromethane (DCM) (10 mL) was added a solution of NBS (0.650 g, 3.65 mmol) in dichloromethane (DCM) (10 mL). The reaction was stirred overnight. The reaction mixture was poured into sodium bicarbonate (saturated aqueous solution, 50 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 24 g silica gel column) to provide 5-bromo-4-fluoro-2,3-dihydro-1 H-indole-1- 1, 1-dimethylethyl carboxylate (1 g, 87% yield) as a mixture (4: 1 LCMS, 10: 1 by H NMR) with the starting material. The mixture was used without further purification. LC-MS (ES) m / z = 260, 262 [M + H-t-Bu] +. 1 H NMR (400 MHz, DMSO-d 6) d 1.51 (s, 9 H), 3.13 (t, J = 8.72 Hz, 2 H), 3.94-4.08 (m, 2 H ), 7.26-7.63 (m, 2 H). 4-Fluoro-5- (4, 4, 5, 5-tetramethyl-1,3, 2-d-oxaborolan-2-yl) -2,3-dihydro-1H-indole-1-carboxylate of 1.1 -dimethylethyl A mixture of 1,1-dimethylethyl 5-bromo-4-fluoro-2,3-dihydro-1 H-indole-1-carboxylate (1 g, 3.16 mmol), adduct of PdCbidpp -Ch ^ Cb (0 , 129 g, 0.155 mmol), potassium acetate (0.776 g, 7.91 mmol) and bis (pinacolato) diboro (0.803 g, 3.16 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature. 100 ° C overnight in a heating plate with stirring. The LCMS analysis indicated the complete conversion to the desired product. The reaction mixture was poured into NaCl (sat. Aq. Solution): H20 1: 1 (100 mL) and ethyl acetate (100 mL), stirred and filtered through Celite. The resulting mixture was separated and the aqueous layer was extracted with two additional portions of ethyl acetate (2 x 50 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAc in hexanes, 40 g silica gel column) to provide 4-fluoro-5- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (660 mg, 57.4% yield) as a pale yellow oil. LC-MS (ES) m / z = 308 [M + H-tBu] +. 1 H-NMR (400 MHz, DMSO-d 6) d 1.29 (s, 12 H), 1.51 (s, 9 H), 3.05 (t, J = 8.72 Hz, 2 H), 3, 98 (t, J = 8.72 Hz, 2 H), 7.22-7.61 (m, 2 H). 5- (4-amino-7-methyl-7H-pyrrolo [2,3-dlpyrimidin-5-yl) -4-fluoro-2,3-dihydro-1 H-indol-1-carboxylate 1,1-dimethylethyl ester A mixture of 5-bromo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (413 mg, 1.817 mmol), 4-fluoro-5- (4,4,5,5) -tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indol-1-carboxylic acid 1,1-dimethylethyl ester (660 mg, 1.817 mmol), Pd2 (dba) 3 (83 mg, 0.091 mmol) and potassium phosphate (K3P04) (771 mg, 3.63 mmol) and (t-Bu) 3PHBF4 (52.7 mg, 0.182 mmol) in 1,4-dioxane (7.5 ml). ) and water (2.5 ml) was stirred at 100 ° C overnight on a heated plate with stirring. The reaction mixture was allowed to cool to room temperature, at which time a yellow crystalline precipitate was observed. The organic layer was separated, the aqueous one was diluted with water (10 ml) and extracted with one portion of ethyl acetate (1 x 30 ml) and two portions of DCM-MeOH (9: 1, xx 30 ml) to solubilize the solids. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was adsorbed on silica and purified by flash chromatography (EtOAc in 0-100% hexanes - >; MeOH in 0-10% DCM, 40 g silica gel column) to give 5- (4-amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4 Fluorine-2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (441 mg, 63.3% yield) as an off-white solid. LC-MS (ES) m / z = 384 [M + H] +. 1 H-NMR (400 MHz, DMSO-d 6) d ppm 1.53 (s, 9 H), 3.15 (t, J = 8.46 Hz, 2 H), 3.75 (s, 3 H), 4 , 03 (t, J = 8.59 Hz, 2 H), 5.88 - 6.12 (m, 2 H), 7.12 - 7.22 (m, 1 H), 7.25 (s, 1 H), 7.44-7.72 (m, 1 H), 8.15 (s, 1 H). 5- (4-fluoro-2, 3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolof2.3-dlpyrimidin-4-amine A suspension of 5- (4-amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4-fluoro-2,3-dihydro-1H-indole-1-carboxylate of 1,1-dimethylethyl (430 mg, 1.121 mmol) and HCl (4 M, dioxane) (10 mL, 329 mmol) was stirred at room temperature overnight. The LCMS analysis indicated that the reaction had been completed, whereby the reaction mixture was filtered and the residue was washed with dioxane (10 ml) and dried in the pump to provide the 5- (4-fluoro-2, 3-dihydro-1 H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (314 mg, 79% yield) as an off-white solid . LC-MS (ES) m / z = 284 [M + H] +. 1 H NMR (600 MHz, DMSO-d 6) d ppm 3.14 (t, J = 7.93 Hz, 2 H), 3.68 (t, J = 7.90 Hz, 2 H), 3.84 ( s, 3 H), 6.83 (broad s, 1 H), 7, 16 (t, J = 6.99 Hz, 1 H), 7.59 (s, 1 H), 8.49 (s, 1 HOUR). 5-r4-fluoro-1- (phenylacetyl) -2, 3-dihydro-1 H-indol-5-ill-7-methyl-7H-pyrrolo [2,3-dlpyrimidin-4-amine A solution of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (100 mg 0.281 mmol), phenylacetic acid (38.2 mg, 0.282 mmol), HATU (107 mg, 0.281 mmol), DIEA (0.196 mL, 1.23 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 ml) and stirred for 30 min and a precipitate formed. The precipitate was collected by filtration and the residue was washed with water, then dried in the pump for one hour, then adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to give 5- [4-fluoro-1- (phenylacetyl) -2,3-dihydro-1 H-indole-5- il] -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (80.2 mg, 71.2% yield) as a white solid. LC-MS (ES) m / z = 402 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.24 (t, J = 8.46 Hz, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 4 , 29 (t, J = 8.46 Hz, 2 H), 5.79-6.20 (m, 2 H), 7.10-7.42 (m, 7 H), 7.95 (d, J = 8.08 Hz, 1 H), 8, 15 (s, 1 H).

EXAMPLE 113 5- Fluoro-1-r (1-methyl-1-pyrrol-2-yl) acetin-2,3-dihydro-1H-indol-5-yl ^ methyl-7H-pyrrolof2.3-crlpyrimidin-4-amine A solution of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (100 mg , 0.281 mmol), (1-methyl-1 H-pyrrol-2-yl) acetic acid (39.1 mg, 0.282 mmol), HATU (107 mg, 0.281 mmol) and DIEA (0.245 mL, 1, 404 mmol) it was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 ml) and stirred for 30 min and a precipitate formed. The precipitate was collected by filtration and the residue was washed with water, then dried in the pump for one hour, then adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to give the . { 4-fluoro-1 - [(1-methyl-H-pyrrol-2-yl) acetyl] -2,3-dihydro-1 H -indole-Si ^ -y-methyl-H-pyrrolo ^^ -dlpyrimidin ^ - amine (70 mg, 61.7% yield) as an off-white solid. LC-MS (ES) m / z = 405 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.25 (t, = 8.34 Hz, 2 H), 3.54 (s, 3 H), 3.69 - 3.79 (m, 3 H) ), 3.87 (s, 2 H), 4.33 (t, v / = 8.34 Hz, 2 H), 5.82 - 5.95 (m, 2 H), 5.95 - 6, 19 (m, 2 H), 6.69 (t, J = 2.27 Hz, 1 H), 7.16-7.24 (m.h. H), 7.26 (s, 1 H), 7 , 93 (d, J = 8.08 Hz, 1 H), 8, 15 (s, 1 H).

EXAMPLE 114 5- (1-r (2,5-difluorophenyl) acetin-4-fluoro-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-lpyrimidin-4-amine A solution of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (100 mg 0.281 mmol), 2,5-difluorophenylacetic acid (48.3 mg, 0.282 mmol), HATU (107 mg, 0.282 mmol) and DIEA (0.196 mL, 1. 123 mmol) was stirred at room temperature overnight . The reaction mixture was poured into water (10 ml) and a precipitate formed. The precipitate was collected by filtration and dried in the pump for 1 hour. The residue was adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to provide 5-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indoi-5-yl > 7-methyl-7H-pyrrolo [2 d] pyrimidin-4-amine (44.2 mg, 36.0% yield) as a white solid. LC-MS (ES) m / z = 438 [M + H] +. 1 H NMR (400 MHz, DMSO-c 6) d ppm 3.23-2.29 (m, 2 H), 3.75 (s, 3 H), 3.97 (s, 2 H), 4.36 ( t, J = 8.34 Hz, 2 H), 5.78 -6.19 (m, 2 H), 7.13-7.32 (m, 5 H), 7.89 (d, J = 8 , 08 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 115 5-f1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl > furor2,3- dlpyrimidin-4-amine 1 - . 1- (1-acetyl-2,3-dihydro-1 H-indol-5-yl) -2-bromoethanone To a suspension of 1,5-diacetylindoline (10.0 g, 49.2 mmol) in 90 ml of THF at t.a. pyridinium tribromide (16.52 g, 51.7 mmol, 1 equiv) was added as a solid in portions over a period of 10 min. When there were still about 1.5 g of pyridinium tribromide remaining, the mixture solidified. Another 30 ml of THF was added to make the mixture stir again. The remaining 1.5 g of tribromide were added in one portion. The mixture was stirred at t.a. (without exothermic reaction checked by a thermometer). After 1.5 h, LC S analysis showed complete conversion. The suspension was filtered. The filter cake was washed with THF (2x 30 ml) and then water (2x 50 ml). The wet filter cake was filtered with suction with laboratory vacuum system at t.a. for 2 days to give 1- (1-acetyl-2,3-dihydro-1 H-indol-5-yl) -2-bromoethanone (12.89 g) as a light gray solid. LC-MS (ES) m / z = 281, 9, 283.9. 1- (1-acetyl-2, 3-dihydro-1H-indol-5-yl) -2-hydroxyethanone To a solid mixture of 1- (1-acetyl-2,3-dihydro-1 H-indole-5- il) -2-bromoethanone (1.0 g, 3.54 mmol) and sodium acetate (1.45 g, 17.71 mmol, 5 equiv) in a 40 ml vial was added EtOH (8 ml) and water ( 8 mi). The resulting suspension was heated in an oil bath at 70 ° C for 3.5 hours. The mixture was cooled in an ice bath, to which 0.7 ml of 6 N NaOH was added. After 2 h, the cold mixture was quenched with 2 ml of 1 N HCl and then concentrated in vacuo. The residue was partitioned between MeOH in 10% DCM and water. The organic layer was dried over Na 2 SO, filtered and concentrated in vacuo. The residue was taken up between DCM and diethyl ether to give a suspension which was filtered. The collected yellow solids were washed with diethyl ether and dried in vacuo to give 1- (1-acetyl-2,3-dihydro-1 H-indol-5-yl) -2-hydroxyethanone (534 mg) as a light yellowish solid, which was used without further purification. 4- (1-acetyl-2, 3-dihydro-1 H-indol-5-yl) -2-amino-3-furanocarbonitrho To a suspension of 1- (1-acetyl-2,3-dihydro-1 H- indol-5-yl) -2-hydroxyethanone (0.53 g, 2.41 mmol) and malononitrile (176 mg, 2.66 mmol, 1.1 equiv) in DMF (4 mL) cooled in an ice bath were diethylamine (380 ul, 3.63 mmol, 1.5 equiv) was added over a period of 3 minutes. The resulting mixture was stirred in the ice bath for another 20 minutes, and then the ice bath was removed. The brown suspension was stirred at room temperature for 2 hours. The LCMS analysis showed that 75% of the product had been formed. To the suspension was added 20 ml of water. The hot suspension was filtered. The filter cake was washed with water and dried with a laboratory vacuum system overnight to give 4- (1-acetyl-2,3-dihydro-1 H -indol-5-yl) -2-amino- 3-furancarbonitrile (360 mg) as a beige solid. LC-MS (ES) m / z = 268 [M + Hf.

[Ethyl 4- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3-cyano-2-furanyl-imidophormate] To a suspension of 4- (1-acetyl-2,3-dihydro-1 H-indol-5-yl) -2-amino-3-furanecarbonitrile (1.248 g, 4.67 mmol) in 1.4- dioxane (12 mL) was added methyl bis (ethyloxy) acetate (2 mL, 12.29 mmol, 2.63 equiv) in one portion. The resulting suspension was heated in an oil bath at 60 ° C. After 15 minutes heating, the mixture was transformed into a solution. Heating was continued for 4 hours and the mixture was cooled to room temperature. After 10 hours of aging at temperature environment, the mixture became a suspension. The LCMS analysis showed the complete conversion. The pulp suspension was combined with a previous experiment (11.1 mg of starting material 4- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -2-amino-3-furanocarbonitrile used ) and filtered. The filter cake was washed with hexane and dried in vacuo (1.20 g) as a brown solid. 1 H-NMR (400 MHz, DMSO-d 6) d ppm 1.34 (t, J = 7.1 Hz, 3 H), 2.18 (s, 3 H), 3.19 (t, J = 8.6 Hz, 2 H), 4, 14 (t, J = 8.6 Hz, 2 H), 4.38 (q, J = 6.6 Hz, 2 H), 7.38 -7.47 (m, 1 H), 7.49 (s, 1 H), 7.94 (s, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 8.64 (s, 1 H) . 5- (1-acetyl-2,3-dihydro-1 H-indol-5-yl) furoy2.3-dlDiimidine-4-amine To a homogeneous dark brown solution of [4- (1-acetyl-2,3-dihydro- 1 / - / - indol-5-yl) -3-cyano-2-furanyl] ethyl imidoformate (2.34 g, 7.24 mmol) in 20 mL of DCM was added 6 mL of 7 N NH3 in MeOH in a portion. The resulting mixture was stirred at room temperature. After 10 minutes, the mixture was transformed into a suspension. After 18 h, the LCMS analysis showed complete conversion. The suspension was concentrated in vacuo, and the residue was dried under vacuum to give 5- (1-acetyl-2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4 -amine (1.92 g, 90% yield) in the form of a beige solid. LC-MS (ES) m / z = 294.9 [M + H] +. 5- (2,3-dihydro-1 H-indol-5-yl) furo [2,3-dlpyrimidin-4-amine] A dark brown suspension of 5- (1-acetyl-2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4-amine (1.71 g, 5.81 mmol ) and LiOH.H20 (5.50 g, 131 mmol, 22.6 equiv) in 50 ml of EtOH and 10 ml of water and 10 ml of DMSO were degassed and flushed with nitrogen. This cycle was repeated 4x, and the mixture was heated in an oil bath at 100 ° C for 48 h. The LCMR analysis showed that there was still 22% starting material left. KOH (MW: 56.11, 3.26 g, 58.1 mmol, 10 equiv) was added to the mixture in the form of pellets. The suspension was degassed and heated at 100 ° C for another 16 h. The LCMS analysis showed that there was no starting product left. The mixture was cooled and filtered. The filter cake was rinsed with 30 ml EtOH. The filtrate was cooled in an ice bath. The pH was adjusted by adding cold 6N HCl to 7-8. The resulting brownish mixture was concentrated in vacuo. The residue was collected in water, but did not form solids. This mixture was concentrated in vacuo again to remove as much solvent as possible (water bath temperature at 65 ° C and vacuum at 3 torr). The solid residue was taken up in water to give a suspension, which was cooled in the refrigerator, followed by filtration. The filter cake was washed with water (2x 8 ml) and dried with laboratory vacuum system for 5 h and then under vacuum over P205 for 15 h to provide 5- (2,3-dihydro-H-indole-5). -yl) furo [2,3-d] pyrimidin-4-amine (0.76 g) as a dark brown solid. LC-MS (ES) m / z = 252.9 [M + H] +. 5-. { 1-f (2,5-difluorophenyl) acetill-2,3-dihydro-1 H-indol-5-yl} furo [2,3-dlpyrimidin-4-amine] To a dark stirred brown solution of 5- (2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4-amine (360 mg, 1.43 mmol) and HATU ( 597 mg, 1.57 mmol, 1.1 equiv) in 3 ml of DMF was added DIEA (274 ul, 1.57 mmol, 1.1 equiv). To this mixture was added (2,5-difluorophenyl) acetic acid in portions (246 mg total, 1.43 mmol, 1 equiv) over a period of 1 h. The mixture was stirred for another 2 h and then added to 50 ml of ice water. The resulting suspension was filtered. The brownish filter cake was washed with water (2x 10 ml) and then suctioned with a laboratory vacuum system for 20 h to give the crude product (760 mg). This material was dissolved in MeOH in 10% DCM and adsorbed on a dry loading cartridge. The purification was done in a silica gel cartridge SF25-60 g using elution with gradient of 1% A to 55% A (A was a mixture of 3200 ml of DCM, 800 ml of MeOH and 80 ml of concentrated NH4OH ). The desired product elutes in 29-32%. Each fraction was checked by LCMS and the 2 pure fractions were combined with the impure product from a previous experiment and concentrated in vacuo. The residue was dissolved in MeOH in 10% CHCl3 and filtered. The filtrate was concentrated in vacuo. The residue was taken up in 1.5 mL of CHC and MTBE (1 mL) and hexane (7 mL) were added to give a suspension which was filtered. The filter cake was washed with hexane (2 × 4 ml) and then dried under vacuum at 65 ° C for 18 h to provide 5-. { 1 - [(2, 5-d if luorofen il) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} furo [2,3-cf] pyrimidin-4-amine (295 mg) as an off-white solid. The NMR, LCMS and HPLC analysis showed that this sample was pure. LC-MS (ES) m / z = 407 [M + H] +. H-NMR (400 MHz, DMSO-cfe) d ppm 3.28 (t, J = 8.6 Hz, 2 H), 3.96 (s, 3 H), 4.30 (t, J = 8.5) Hz, 2 H), 7, 13 - 7.28 (m, 3 H), 7.30 (d, J = 9.1 Hz, 1 H), 7.40 (s, 1 H), 7.93 (s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 8.25 (s, 1 H), the NH2 protons are not visible.

EXAMPLE 116 5- (1- (r3- (Trifluoromethyl) phenynacetyl-2,3-dihydro-1H-indol-5-yl) furor-2,3-dlpyrimidin-4-amine To a stirred dark greenish solution of 5- (2,3-dihydro-1H-indol-5-yl) furo [2,3-d] pyrimidin-4-amine (400 mg, 1.59 mmol) and HATU (663 mg, 1.74 mmol, 1.1 equiv) in 4 ml of DMF was added DIEA (305 ul, 1.74 mmol, 1.1 equiv). To this mixture was added [3- (trifluoromethyl) phenyl] acetic acid in portions (324 mg total, 1.59 mmol, 1 equiv), approximately 80 mg at 30 min intervals. After a total of 3 h, the LCMS analysis showed that there was still 16% starting material, per UV. The mixture was diluted with ice-cold water (40 ml) to give a dark greenish suspension, which was filtered. The filter cake was washed with water (2x 8 ml), and suction filtered with laboratory vacuum system for 18 h to provide the crude product (900 mg), which was dissolved in DCM in 10% MeOH and adsorbed on a dry charge cartridge. Purification was done on a silica gel cartridge SF25-60 g using gradient elution of 1% A to A in 50% DCM (A was a mixture of 3200 ml of DCM, 800 ml of MeOH and 80 ml of Concentrated NH 4 OH). The product eluted around A at 25-30%. The fractions with product were combined and concentrated in vacuo. This material contained an impurity, and the residue was subjected to another purification on silica gel in a silica gel cartridge SF25-80 g using gradient elution of B in 1% EtOAc to 50% B (B was a mixture of MeOH in 10% EtOAc). The desired product eluted in 10-13% B. The pure fractions were combined and evaporated. The residue (200 mg) was taken up in CHC (0.45 ml), MTBE (3 ml) and hexane (3 ml) to give a suspension, which was filtered. The solids were washed with hexane (2x3 mL) and dried under vacuum at 65 ° C for 18 h to provide 5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2.3. -dihydro-1 / - / - indol-5-yl) furo [2,3-d] pyrimidin-4-amine (170 mg) as a light cream solid. LC-MS (ES) m / z = 439 [M + H] +. H-NMR (400 MHz, DMSO-cfe) d ppm 3.27 (t, J = 8.3 Hz, 2 H), 4.05 (s, 2 H), 4.28 (t, J = 8.6) Hz, 2 H), 7.30 (d, J = 8.1 Hz, 1 H), 7.39 (s, 1 H), 7.56 - 7.66 (m, 3 H), 7.68 (s, 1 H), 7.93 (s, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 8.25 (s, 1 H), NH2 protons are not visible or appear as a broad shoulder.

EXAMPLE 117 5- (1-r (3-chloro-5-fluorophenyl) acetin-2,3-dihydro-1 H-indol-5-yl> furor 2,3-cnpyrimidin-4-amine To a stirred dark greenish solution of 5- (2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU ( 829 mg, 2.18 mmol, 1.1 equiv) in 5 ml of DMF was added DIEA (381 ul, 2.18 mmol, 1.1 equiv). To this mixture was added (3-chloro-5-fluorophenyl) acetic acid in portions (374 mg total, 1.98 mmol, 1 equiv), approximately 130 mg at 30 min intervals. After 2 h, the LCMS analysis showed complete conversion. The mixture was poured into 50 mL of ice-cold water to give a suspension which was filtered. The filter cake was washed with water (2x10 ml), and dried with a laboratory vacuum system for 18 h to provide the crude product (1.0 mg), which was dissolved in MeOH in 10% DCM and adsorbed on a dry charge cartridge. The purification was done in a silica gel cartridge SF25-60 g using elution with gradient of A in 1% DCM to A in 50% DCM (A was a mixture of DCM / MeOH / NH4OH 3200/800/80) . The desired product eluted impure with A at 24-30%. The fractions containing product were combined and concentrated in vacuo, and re-adsorbed in a dry loading cartridge. Purification was done on a silica gel cartridge SF25-80 g using gradient elution of 1% A to A in 75% EtOAc (B was MeOH in 2.5% EtOAc). Two fractions were collected. The first fraction eluted in B at 15-35% as an acute peak which was concentrated in vacuo. The residue was taken up in CHCl3 (2 mL) and MTBE (6 mL) as a suspension which was filtered. The solids they were washed with MTBE (2x 3 ml) and hexane (2x 3 ml). The second fraction eluted in B at 63-100% as a broad peak. The large volume of eluted solvent was concentrated in vacuo. This residue was taken up in CHCl3 (2 mL) and MTBE (8 mL) as a suspension that was filtered. The filter cake was washed with MTBE (2x 3 ml) and hexane (3x 4 ml). The solids were combined with the previous solids of the first fraction and dried under vacuum at 65 ° C for 18 h to provide the 5-. { 1 - [(3-chloro-5-fluorophenol) acetyl] -2, 3-dihydro-1 H-indol-5-yl} furo [2,3-d] pyrimidin-4-amine (492 mg) as an off-white solid. LC-MS (ES) m / z = 423 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.26 (t, J = 8.3 Hz, 2 H), 3.97 (s, 2 H), 4.25 (t, J = 8.5 Hz, 2 H), 7.18 (d, J = 9.9 Hz, 1 H), 7.27 (s, 1 H), 7.29 - 7.38 (m, 2 H), 7.39 (s, 1 H), 7.93 (s, 1 H), 8.15 (d, J = 8, 1 Hz, 1 H), 8.25 (s, 1 H), the NH2 protons are not visible.

EXAMPLE 118 5- (1-r (3-methylphenyl) acetn-2,3-dihydro-1 ^ amine To a stirred dark greenish solution of 5- (2,3-dihydro-1H-indol-5-yl) furo [2,3-d] pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 ml of DMF was added DIEA (381 ul, 2.18 mmol, 1.1 equiv). To this mixture was added (3-methylphenyl) acetic acid in portions (298 mg total, 1.98 mmol, 1 equiv), approximately 100 mg at 30 min intervals. After a total of 2.5 hours, the mixture was poured into 50 ml of ice-cold water to give a suspension which was filtered. The filter cake was washed with water (2x10 ml), and dried with a laboratory vacuum system for 18 h to provide the crude product (1.0 mg), which was dissolved in MeOH in 10% DCM and adsorbed on a dry charge cartridge. The first purification was done on a silica gel cartridge SF25-60 g using gradient elution of A in 1% DCM to A in 55% DCM (A was a mixture of DCM / MeOH / NH4OH 3200/800/80 ). The desired product eluted impure in A at 24-30%. The fractions were combined and concentrated in vacuo, and re-absorbed in a dry charge cartridge. The second purification was done on a silica gel cartridge SF25-80 g using elution with gradient of 1% B to B in 100% EtOAc (B was MeOH in 2.5% EtOAc). The fractions with the pure desired product were combined and concentrated in vacuo. The residue was taken up in CHCl3 (1 mL) and MTBE (7 mL) to give a suspension which was filtered. The filter cake was washed with MTBE (2x3 mL) and hexane (3x3 mL), and dried under vacuum at 65 ° C to provide the 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [2,3-c] pyrimiclin-4-arnine (431 mg) as a beige solid. LC-MS (ES) m / z = 385 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.31 (s, 3 H), 3.22 (t, J = 8.5 Hz, 2 H), 3.84 (s, 2 H), 4 , 22 (t, J = 8.6 Hz, 2 H), 7.04 - 7.15 (m, 3 H), 7, 19 - 7.26 (m, 1 H), 7.30 (d, J = 8.3 Hz, 1 H), 7.37 (s, 1 H), 7.92 (s, 1 H), 8.18 (d, J = 8.3 Hz, 1 H), 8, 25 (s, 1 H), the NH2 protons were not visible.

EXAMPLE 119 5- (1- (R3-Fluoro-5- (trifluoromethyl) phenynacetyl) -2.3-dihydro-1H-indol-5-yl) furof2,3-dlpyrimidin-4-amine To a stirred dark greenish solution of 5- (2,3-dihydro-1 H -indol-5-yl) furo [2,3-d] pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU ( 829 mg, 2.18 mmol, 1.1 equiv) in 5 ml of DMF was added DIEA (381 ul, 2.18 mmol, 1.1 equiv). To this mixture was added [3-fluoro-5- (trifluoromethyl) phenyl] acetic acid in portions (440 mg total, 1.98 mmol, 1 equiv), approximately 10 mg at 30 min intervals. After a total of 2.5 hours, the mixture was poured into 50 ml of ice-cold water to give a suspension which was filtered. The filter cake was washed with water (2x 15 ml), and dried with laboratory vacuum system at t a. for 18 h to provide the crude product (1.0 mg), which was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on a silica gel cartridge of SF25-60 g using gradient elution of A in 1% DCM to A in 50% DCM (A was a mixture of DCM / MeOH / NH4OH 3200/800/80 ). The desired product eluted impure with A at 25-30%. These fractions were combined and concentrated in vacuo. The residue was redissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. A second purification was made on a silica gel cartridge SF25-80 g using elution with gradient of 1% B to B in 100% EtOAc (B was a mixture of MeOH in 2.5% EtOAc). Note: the product was very soluble in EtOAc. Two fractions were collected. The first fraction eluted in B at 8-12%. The second fraction eluted in B at 33-100%. Both were pure by TLC. They were combined and concentrated in vacuo. The residue was taken up in CHCl3 (3 mL) and MTBE (7 mL) as a suspension that was filtered. The solids were washed with MTBE (2x 3 mL) and hexane (3x 4 mL) and dried under vacuum at 65 ° C for 18 h to provide 5- (1- {3-fluoro-5- (trifluoromethyl) Phenyl] acetyl} -2,3-dihydro-1 / - / - indol-5-yl) furo [2,3-d] pyrimidin-4-amine (445 mg) as a beige solid. LC-MS (ES) m / z = 457 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.28 (t, J = 8.5 Hz, 2 H), 4.08 (s, 2 H), 4.28 (t, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.40 (s, 1 H), 7.51 (d, J = 9.9 Hz, 1 H), 7.57 (s, 1 H), 7.60 (d, J = 8, 1 Hz) , 7.93 (s, 1 H), 8, 14 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H), the protons of NH2 were not visible.

EXAMPLE 120 5- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7-r2- (4-piperidinyl) etin-7H-pyrrolof2,3-t / lpyrimidin-4-amine 4- [2- (5-bromo-4-chloro-7H-pyrrolo [2,3-d-pyrimidin-7-yl) ethyl] -1-piperidinecarboxylate 1,1-dimethylethyl ester To 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyrimidine (200 mg, 0.860 mmol) in tetrahydrofuran (THF) (10 mL) was added 4- (2-hydroxyethyl) -1- 1, 1-dimethylethyl piperidinecarboxylate (592 mg, 2.58 mmol) and resin with polymer-bound triphenylphosphine (574 mg, 1.721 mmol). Then, DEAD (0.222 ml, 1.721 mmol) was added dropwise to the mixture. Then, the stirring bar was removed from the reaction, and the reaction was then placed on a horizontal stirrer and the reaction was stirred at room temperature overnight. The resin was filtered off and the filtrate was concentrated and then loaded onto a 10 g Biotage SNAP column and eluted with EtOAc in hexane of 0. to 45% to give 4- [2- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimin-7-1) etl] -1 - 1, 1-dimethylethyl piperidinecarboxylate (326 mg, 85% yield) as a white solid. LC-MS (ES) m / z = 443.4 [M + H] +. 4- [2- (4-amino-5-bromo-7H-pyrroloyl-2,3-dloirimidin-7-yl) ethyl-1-piperidinecarboxylate 1,1-dimethylethyl ester To 4- [2- (5-bromo-4-chloro-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (320 mg, 0.721 mmol) in a 5 ml vial with a hermetic seal was added ammonium hydroxide (1.5 ml, 38.5 mmol). Then the vial was capped and heated at 90 ° C overnight. Then, the reaction was cooled and the solid was isolated by filtration and washed with NH 4 OH. The solid was then air dried to give 4- [2- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] -1-piperidinecarboxylate of 1.1. -dimethylethyl (309 mg) as an off-white solid containing a small amount of starting material. It was used without further purification. LC-MS (ES) m / z = 424.4 [M + H] +. 4- [2- (4-amino-5-. {-1-1 (2,5-difluorophenyl) acetyl-2,3-dihydro-1 H-indol-5-yl.} - 7 H -pyrrolo [2,3- 1,1-dimethylethyl 1,1-piperidin-7-yl) etill-1-piperidine Al 4-1-, 4-dimethylethyl 4- (2- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] -1-piperidinecarboxylate (220 mg, 0.518 mmol) and 1 - [(2,5-difluorophenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H - indole (290 mg, 0.726 mmol) in a 5 ml vial with a tight seal, 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (1 ml) were added. The mixture was then bubbled with N? for 10 minutes, then Pd (Ph3P) 4 (59.9 mg, 0.052 mmol) was added and N2 was bubbled for 5 minutes. The mixture was then capped and heated to 100 ° C. After 4 hours the reaction was complete. The reaction was diluted with water (5 mL) and then extracted with EtOAc (3x10 mL). The organic extracts were combined, washed with brine and dried over MgSO4, filtered and concentrated. The crude oil was then dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u 018 (2) 100A column, 50x30.00 mm 5 microns, experiment 7, 3 minutes (47 ml / min, ACN / 2% H2O, 0.1% TFA to ACN / 32% H2O, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO 3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred to a 40 ml vial with MeCN, then water was added and lyophilized to isolate 4- [2- (4-amino-5-. {1 - [(2,5-difluorophenyl) acetyl] ] -2,3-dihydro-1 H -indol-5-yl.} - 7-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] -1-piperidinecarboxylate 1,1-dimethylethyl ester (151 mg, 47.2% yield) in the form of a white powder. LC-MS (ES) m / z = 617.6 [M + H] +. 5-. { 1-α (2,5-d-fluoro-phenyl) -acetyl-2,3-dihydro-1H-indo ^ piperidinyl) etill-7H-pyrrolo [2,3-dlpyrimidin-4-amine Al 4- [2- (4-amino-5- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl.} -7H- 1, 1-dimethylethylpyrrol [2,3-d] pyrimid-7-yl) ethyl] -1-piperidinecarboxylate (157 mg, 0.255 mmol) was added with 4 N HCl (5 ml). , 20.00 mmol) in dioxane and the mixture was allowed to stir at room temperature overnight. The reaction was concentrated and the solid was isolated by filtration and washed with diethyl ether to isolate 115 mg of the desired product as an HCl salt, which was then dissolved in 2 ml of DMSO and purified by HPLC: HPLC: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 micrometers, 7.3 minute experiment (47 ml / min, 10% ACN / H20, 0.1% TFA to 35% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated aHC03 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred to a 40 ml vial with MeCN. Water was added and then lyophilized to give 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl} -7- [2- (4-p.peridinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (16 mg, 88% yield) as a white solid. LC-MS (ES) m / z = 517.6 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.35 (broad s, 1 H), 8.14 (s, 1 H), 8.09 (d, J = 8.08 Hz, 1 H), 7 , 35 (d, J = 4.04 Hz, 2H), 7.15-7.30 (m, 4H), 6.09 (broad s, 2H), 4.29 (t, J = 8.34 Hz) , 2H), 4.21 (t, J = 6.95 Hz, 2H), 3.95 (s, 2H), 3.22-3.30 (m, 4H), 2.77-2.85 ( m, 2H), 1.91 (d, J = 12.13 Hz, 2H), 1.77 (q, J = 6.65 Hz, 2H), 1.47 (s broad, 1 H), 1, 26-1, 38 (m, 2H).

EXAMPLE 121 pyrrolor2,3-onpyrimidin-4-amine (1,1-dimethyl ethyl 6-methyl-2-pyridinyl) acetate To a stirred solution of tere-butyl acetate (1.013 ml, 7.50 mmol), 2-chloro-6-methylpyridine (638 mg, 5 mmol), chloro (2-di-t-butylphosphino-2). [6'-tri - / '- propyl-1, r-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) (34.3 mg, 0.050 mmol) in toluene (10 ml) at 0 ° C in a 100 ml round bottom flask under N2 atmosphere was added a solution of LHMDS (1 M in toluene) (15.00 ml, 15.00 mmol) previously cooled to 0 ° C. The reaction was stirred for 30 minutes. The LCMS analysis indicated that the reaction was complete, so it was poured into ammonium chloride (aqueous, saturated solution) and water (1: 1, 40 ml), and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAc in hexanes) to give the 1,1-dimethylethyl (6-methyl-2-pyridinyl) acetate (918 mg, 4.43 mmol, 89% yield) in shape of a yellow oil. LC-MS (ES) m / z = 208 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 1.41 (s, 9 H), 2.44 (s, 3 H), 3.68 (s, 1 H), 7.12 (t, J = 7.33 Hz, 2 H), 7.64 (t, J = 7.71 Hz, 1 H).

Salt of (6-methyl-2-pyridinyl) acetic acid trifluoroacetate To a solution of 1,1-dimethylethyl (6-methyl-2-pyridinyl) acetate (71 1 mg, 3.43 mmol), triethylsilane (1. 370 ml, 8.58 mmol) in dichloromethane (DCM) mi) TFA (3.44 mL, 44.6 mmol) was added dropwise via syringe. The reaction was stirred overnight at room temperature. The LCMS analysis indicated a good conversion, whereby the reaction was concentrated to a colorless oil and diethyl ether (6 ml) was added. A white precipitate formed which was collected by filtration, dried in the pump for 10 min, and then under high vacuum to provide the TFA salt of (6-methyl-2-pyridinyl) acetic acid (771 mg) in the form of a white solid. LC-MS (ES) m / z = 152 [M + H] +. 1 H NMR (400 MHz, DMSO-c / 6) d ppm 2.62 (s, 3 H), 3.95 (s, 2 H), 7.54 (d, J = 7.33 Hz, 2 H) , 8.1 1 (broad s, 1 H). 7-methyl-5-. { 1 (6-methyl-2-pyridinyl) acetill-2 ^ 7H-pyrrolof2,3-dlpyrimidin-4-amine A solution of 5- (2,3-dihydro-H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (150 mg, 0.443 mmol), TFA salt from (6-methyl-2-pyridinyl) acetic acid (1 18 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.387 mL, 2.217 mmol) in?,? - dimethylformamide (DMF) ( 3 ml) was stirred overnight at room temperature. At this time the LCMS analysis indicated complete conversion, whereby water (15 ml) was added to the mixture reaction, and the resulting mixture was stirred for 30 minutes at room temperature, forming an emulsion-like mixture. The mixture was extracted with ethyl acetate: methanol (approximately 1% methanol, 3 x 30 mL) and the combiorganic extracts were dried over sodium sulfate, filtered and concentrated. The residue was adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc, 12 g column) to give 7-methyl-5. { 1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (167.3 mg, 0.420 mmol, 95% yield) as an off-white solid. LC-MS (ES) m / z = 399 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 2.46 (s, 3 H), 3.23 (t, J = 8.34 Hz, 2 H), 3.75 (s, 3 H), 4 , 00 (s, 2 H), 4.29 (t, J = 8.46 Hz, 2 H), 6.01 - 6.41 (m, 2 H), 7, 17 (t, = 7.33 Hz, 2 H), 7.23 (d, J = 8.34 Hz, 1 H), 7.27-7.34 (m, 2 H), 7.68 (t, J = 7.58 Hz, 1 H), 8.12 (d, J = 8.08 Hz, 1 H), 8.18 (s, 1 H).

EXAMPLE 122 5. (1 . { R4.fluoro-3- (trifluoromethyl) phenynacetyl > -2.3-dihydro-1 fí-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-cnpyrimidin-4-amine A solution of 5- (4-fluoro-2,3-dihydro-H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amino .2HCl (150 mg, 0.443 mmol), [4-fluoro-3- (trifluoromethyl) phenyl] acetic acid (99 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol) and DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The LCMS analysis indicated a good conversion, whereby the resulting suspension was poured into water (10 ml) and stirred for 30 min, forming a precipitate. The precipitate was collected by filtration, dried in the pump for 1 hour, then adsorbed on silica and purified by flash chromatography (MeOH in 0-8% EtOAc, 12 g column) to give the 5- (1- { [4-fluoro-3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (198 mg, 95% yield) as a white solid. LC-MS (ES) m / z = 470 [M + H] +. 1 H NMR (400 MHz, DMSO-cfe) d ppm 3.26 (t, J = 8.46 Hz, 2 H), 3.74 (s, 3 H), 4.02 (s, 2 H), 4 , 27 (t, J = 8.34 Hz, 2 H), 5.91 - 6.20 (m, 2 H), 7.19 - 7.29 (m, 2 H), 7.33 (s, 1 H), 7.50 (t, J = 9.73 Hz, 1 H), 7.64-7.70 (m, 1 H), 7.73 (d, J = 6.57 Hz, 1 H ), 8.1 1 (d, = 8.34 Hz, 1 H), 8.15 (s, 1 H).

EXAMPLE 123 5- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl) -7- (3-oxetanyl) pyrrolor2,3- (lpyrimidin-4-amine 5-bromo-4-chloro-7- (3-oxetanyl) -7H-pyrrolo [2,3-d-pyrimidine] To the 5-bromo-4-chloro-1 H -pyrrolo [2,3-d] pyridine (300 mg, 1.291 mmol) was added 3-oxethanol (287 mg, 3.87 mmol ), resin with polymer-bound triphenylphosphine (860 mg, 2.58 mmol) and, 4-dioxane (2 ml) in a 5 ml microwave vial and then DEAD (0.409 ml, 2.58 mmol) was added. Then, the reaction vial was capped and heated in a microwave reactor for 15 minutes at 85 ° C. The reaction was not complete so it was heated for a total of 1 h and the reaction was filtered, concentrated, diluted with EtOAc (10 mL) and then washed with water (10 mL). The water was back extracted with EtOAc (2 x 10 mL). Then the organic extracts were combi then washed with brine, dried over MgSO4, filtered and concentrated. The crude product was loaded onto a 10 g Biotage column and purified with gradient EtOAc in hexane from 0 to 40% at 30 minutes to give a 5-bromo-4-chloro-7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidine (157 mg, 42.2% yield) as a solid White. 1 H NMR (400 MHz, DMSO-d 6) d 8.70 (s, 1 H), 8.45 (s, 1 H), 5.95 (t, J = 7.07 Hz, 1 H), 4, 96 - 5.04 (m, J = 7.07, 7.33, 7.45, 7.45 Hz, 4H). 5-bromo-7- (3-oxetanyl) -7H-pyrrolo [2,3-dlpyrimidin-4-amine] To 5-bromo-4-chloro-7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidine (185 mg, 0.641 mmol) was added ammonium hydroxide (24.97 μ ?, 0.641 mmol) in a 25 ml sealed vial and heated at 85 ° C for 24 h. The solid was isolated by filtration and washed with water (5 ml) and dried to give 5-bromo-7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (106 mg), which was used without further purification. 5- ^^ 2,5-d / f / tyorofen / 7) aceW / -2,3-d / 7? / Dro-fH- / ndo / -5 - // -7- 3-oxetanyl) -7H- pyrrolof2, 3-dlpyrimidin-4-amine To 5-bromo-7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.186 mmol) and 1 - [(2,5-difluorophenyl) acetyl] - 5- (4,4,5l5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (104 mg, 0.260 mmol) was added 1,4-dioxane (2 mi) and saturated NaHCO 3 solution (1 ml) in a 5 ml vial with airtight seal. N 2 gas was bubbled through the mixture for 10 minutes, then Pd (Ph 3 P) 4 (21.47 mg, 0.019 mmol) was added and N 2 was bubbled for 5 minutes. The mixture was then capped and heated at 100 ° C overnight. The reaction was diluted with water (3 mL) and then extracted with EtOAc (4x5 mL). Then the organic extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was then diluted with 3 mL of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minute experiment (47 ml / min, ACN / 15% H20, 0.1% TFA at 40% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO 3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO, filtered and concentrated. Then the material was transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to give the 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (53 mg, 61.8% yield) as a white powder. LC-MS (ES) m / z = 462.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.15 (d, J = 3.28 Hz, 1 H), 8.08 - 8, 13 (m, 1 H), 7.70 (d, J = 3.03 Hz, 1 H), 7.41 (broad s, 1 H), 7.15 - 7.33 (m, 4H), 6, 17 (broad s, 2H), 5.82 - 5.93 (m, 1 H), 4.95 -5.07 (m, 4H), 4.30 (broad s, 2H), 3.96 (broad s, 2H), 3.29 (d, J = 1, 01 Hz, 2H).

EXAMPLE 124 3- (1-r (2,5-difluorophenyl) acetun-2,3-dihydro-1H-indol-5-yl) -7-r 2 - (dimethylamino) ethyl 1-fluoride 3,2-c-pyridin-4-amine A solution of 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} Furo [3,2-c] pyridin-4-amine (182 mg, 0.386 mmol) in tetrahydrofuran (THF) (5 ml) and methanol (2.5 ml) under nitrogen atmosphere was cooled to 0 ° C. Formaldehyde (37% by weight in water) (61 μ ?, 0.812 mmol) was added, and after about 5 minutes sodium triacetoxyborohydride (327 mg, 1.542 mmol) was added in one portion. The reaction mixture was allowed to slowly warm to room temperature and was stirred for 21 hours. The mixture was then poured into saturated aqueous NaHCO 3 solution (20 ml), diluted with a little water, and extracted with ethyl acetate (2 * 20 ml). The extracts were washed with brine (1 * 20 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g of S1O2, gradient from DCM to DCM / MeOH / NH4OH 90/10/1 over 40 minutes) to give the 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- [2- (dimethylamino) ethyl] furo [3,2-c] pyridin-4-amino (122 mg, 66.4% yield) as a yellow solid. LC-MS (ES) m / z = 477 [M + Hf. 1 H NMR (400 MHz, DMSO-de) d ppm 2.20 (s, 6 H), 2.83 (t, J = 7.58 Hz, 2 H), 3.28 (t, J = 8.34) Hz, 2 H), 3.96 (s, 2 H), 4.30 (t, J = 8.34 Hz, 2 H), 5.33 (s, 2 H), 7.04 - 7.36 (m, 4 H), 7.41 (s, 1 H), 7.72 (s, 1 H), 7.93 (s, 1 H), 8.12 (d, J = 8.34 Hz, 1 HOUR). Note: NHs are not observed.

EXAMPLE 125 7-methyl-5- (1- { R6- (trifluoromethyl) -2 ^ 7H-pyrrolor2,3-cnpyrimidin-4-amine [1- (dimethyl-ethyl) 6- (trifluoromethyl) -2-pyridin-J-acetate) To a stirred solution of tere-butyl acetate (1.013 ml, 7.5 mmol), 2-chloro-6- (trifluoromethyl) pyridine (908 mg, 5.00 mmol), chlorine (2-di-t- butylphosphino-2 ', 4', 6'-tri-i-propyl-1, '-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) (34.3 mg, 0.500 mmol) in toluene (10). mi) at 0 ° C in a 100 ml round bottom flask under N2 atmosphere was added a solution of LHMDS (1 M in toluene) (15.00 ml, 15.00 mmol) previously cooled to 0 ° C. The reaction was stirred for 30 min, but the LCMS analysis indicated that the reaction had not been completed, so the reaction was allowed to warm to room temperature. overnight, and the LCMS analysis indicated that the reaction had been completed, so it was poured into ammonium chloride (saturated aqueous solution) and water (1: 1, 40 ml), and extracted with ethyl acetate ( 3 x 100 mi). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (EtOAC in 0-25% hexanes, 90 g column) to give [1- (1-dimethylethyl [6- (trifluoromethyl] -2-pyridinyl] acetate (701.3 mg , 53.7% yield) in the form of a pale yellow oil. LC-MS (ES) m / z = 206 [M + H-tBuf. 1 H NMR (400 MHz, DMSO-cfe) d ppm 1.41 (s, 9 H), 3.88 (S, 2 H), 7.61-7.71 (m, 1 H), 7.77- 7.85 (m, 1 H), 8.02 - 8, 11 (m, 1 H). [6- (trifluoromethyl) -2-pyridinyl] acetic acid To a solution of 1,1-dimethylethyl (6- (trifluoromethyl) -2-pyrridinyl) acetate (698 mg, 2.67 mmol), triethylsilane (1.067 mL, 6.68 mmol) in dichloromethane (DCM) ( 10 mL) was added TFA (2.68 mL, 34.7 mmol) dropwise via syringe. The reaction was stirred overnight at room temperature. In LCMS analysis it indicated a good conversion so the reaction was concentrated to a yellow oil. 5 ml of diethyl ether were added but no precipitation occurred, whereby the solution was concentrated to give [6- (trifluoromethyl) -2-pyridinyl] acetic acid (535 mg, 2.61 mmol, 98% yield) in the form of a yellow oil that solidified to a yellow solid. LC-MS (ES) m / z = 206 [M + H] +. H-NMR (400 MHz, DMSO-d6) d ppm 3.89 (s, 2 H), 7.70 (d, J = 7.83 Hz, 1 H), 7.81 (d, J = 7.58) Hz, 1 H), 7.97 - 8.16 (m, 1 H), 12.26 - 12.88 (broad s, 1 H). 7-methyl-5- (1- { [6- (trifluoromethyl) -2-Dirid ^ indol-5-yl) - 7H-pyrrolo [2,3-dlpyrimidin-4-amine A solution of 5- (2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine.2HCl (150 mg, 0.443 mmol) , [6- (trifluoromethyl) -2-pyridinyl] acetic acid (91 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.310 mL, 1.774 mmol) in?,? - dimethylformamide (DMF) (3 mL) was stirred overnight at room temperature. At this time the LCMS analysis indicated a good conversion, whereby the reaction mixture was poured into water (10 ml) and stirred for 30 min. The resulting precipitate was collected by filtration, dried in the pump for 1 hour, adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to provide 7-methyl-5- (1- { [6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine ( 80 mg, 39.9% yield) in the form of a beige solid. LC-MS (ES) m / z = 453 [M + H] +. 1 H NMR (400 MHz, DMSO-c / 6) d ppm 3.26 (t, J = 8.34 Hz, 2 H), 3.74 (s, 3 H), 4.21 (s, 2 H) , 4.31 (t, J = 8.46 Hz, 2 H), 5.85-6.26 (m, 2 H), 7.23 (d, J = 8.34 Hz, 1 H), 7 , 26 (s, 1 H), 7.34 (s, 1 H), 7.71 (d, J = 7.83 Hz, 1 H), 7.83 (d, J = 7.58 Hz, 1 H), 8.05-8.13 (m, 2 H), 8, 15 (s, 1 H).

EXAMPLE 126 7- (3-oxetanyl) -5- (1 - (r3-ftrifluoromethyl) phenynacetyl > -2,3-dihydro-1 H-indol-5H 7H-pyrrolor2,3-cnpyrimidin-4-amine 5-bromo- 1 -. { [3- (trifluoromethyl) phenylacetyl} -2, 3-dihydro-1 H-indole To 5-bromoindoline (5.0 g, 25.2 mmol, 1 equiv) and [3- (trifluoromethyl) phenyl] acetic acid (6.18 g, 30.3 mmol, 1.2 equiv) in 13 ml of DMF was added propylphosphonic anhydride (36.9 ml of a solution 1, 71 M in DMF, 63, 1 mmol, 2.5 equiv) followed by DIEA (8.82 mL, 50.5 mmol, 2 equiv). The reddish mixture became warm to the touch and cooled once in an ice bath. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature. After 18 h, the mixture was diluted with 200 mL of EtOAc and washed with 200 mL of water. The aqueous layer was extracted with 150 ml of EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a paste residue which was taken up in diethyl ether and hexane to provide a suspension. The suspension was filtered. The solids were washed with hexane and then diethyl ether and dried in vacuo to give the crude product (6.17 g) as a tacky brownish solid. The NMR analysis showed the presence of some alkyl impurities, whereby this batch was redissolved in DCM (150 ml) and washed with water (50 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated in DCM (5 ml) and diethyl ether (75 ml). The suspension was filtered and the filter cake was washed with diethyl ether. The solids were dried in vacuo to provide 5-bromo-1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (4.73 g) as a light cream solid. The filtrate was concentrated in vacuo, and the residue was dissolved in DCM and absorbed in a dry charge cartridge. Purification was done in silica gel cartridge SF40-150 g using gradient elution of EtOAc in hexane 1% to EtOAc in 45% hexane. The product peak eluted in 24-33% EtOAc. The product fractions were combined and concentrated in vacuo to give the product (2.80 g) as a brownish tacky solid residue. The analyzes of both NMR and LCMS showed that this lot had some impurities. The residue was triturated in DCM and diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The solids were dried in vacuo to provide 5-bromo-1-. { [3- (trifluoromethyl) phenyl] acetyl} Additional 2,3-dihydro-1 H-indole (1.62 g) as an off-white solid. The analyzes of both NMR and LCMS showed that this lot was pure. LC-MS (ES) m / z = 384 [M + H] +, 386. 1 H NMR (400 MHz, DMSO-de) d ppm 3.20 (t, J = 8.5 Hz, 2 H), 4 , 00 (s, 2 H), 4.23 (t, J = 8.6 Hz, 2 H), 7.32 (dd, J = 8.7, 1, 9 Hz, 1 H), 7.45 (s, 1 H), 7.53-7.70 (m, 4 H), 7.96 (d, J = 8.6 Hz, 1 H). 5- (4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenylacetyl} -2, 3-dihydro-1 H-indole A mixture of 5-bromo-1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (8.50 g, 22.12 mmol, 1 equiv), bis (pinacolato) diboro (6.74 g, 26.5 mmol, 1.2 equiv), adduct of PdCI2 (dppf) -CH2CI2 (1.81 g, 2.21 mmol, 0.1 equiv) and potassium acetate (5.43 g, 55.3 mmol, 2.5 equiv) in 85 ml of dioxane in a flask 500 ml was degassed and a nitrogen sweep was made. This 4x procedure was repeated. The mixture was heated in an oil bath at 100 ° C. The color of the mixture gradually changed from the initial orange to burgundy over a period of 30 min when the temperature reached 100 ° C, and then became darker as heating progressed. After 20 h, the LCMS analysis showed complete conversion. The dark blackish mixture was filtered through Celite. The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (250 mL) and brine (40 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The solid residue was dissolved in DCM. Approximately 1/5 was absorbed in a dry charge cartridge. Purification was done on an Analogix silica gel cartridge SF40-115 g using gradient elution of EtOAc in 1% hexane to EtOAc in 45% hexane. However, the dry charge cartridge was plugged. The back pressure was too high for the Analogix instrument to work and the pump stopped (the sample was not as soluble in hexane). Approximately one half was injected into the silica gel cartridge and the desired product eluted in 24-30% EtOAc in hexane. The clogged dry loading cartridge was washed by sweeping with 100 ml of 100% EtOAc to recover the remainder of the injected sample, which was combined with the other 4/5 of the original DCM sample solution. This mixture was concentrated in vacuo and redissolved in DCM (50 ml), and added to a prepackaged gravity column (250 g thick-quality silica gel packed in DCM in 1% hexane). The column was eluted with 400 ml of DCM in 1% hexane, 400 ml of DCM / hexane 1/3, 400 ml of DCM / hexane 1/1, and then 400 ml of portions of DCM / hexane 1/1 each. with an increase of 20 ml of EtOAc. The desired product eluted in the EtOAc fractions from 20 ml to 60 ml. The collected fractions (including that of the previous Analogix preparation) were combined and concentrated in vacuo to approximately 100 ml of volume as a suspension. This suspension was filtered. The filter cake was washed with hexane (10 mL) and dried under vacuum for 18 h to provide the 5- (4, 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (5.98 g) as a white solid. LC-MS (ES) m / z = 432 [M + Hf. 1 H NMR (400 MHz, DMSO-de) d ppm 1.28 (s, 12 H), 3.19 (t, J = 8.5 Hz, 2 H), 4.02 (s, 2 H), 4 , 23 (t, J = 8.6 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7.56 - 7.69 (m, 14 H), 8.03 (d, J = 8.1 Hz, 1 H). 7- (3-oxetanyl) -5- (1- { R3- (trifluoromethyl) phenylacetyl) - ^ indol-5-yl) -7H-pyrrolof2, 3-dlpyrimidin-4-amine To 5-bromo-7- (3-oxetanyl) -7H-pyrrolo [2,3-d] pyrmidin-4-amino (50 mg, 0.186 mmol) and 5- (4, 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) pheny] acetyl} -2,3-dihydro-1 H -indole (12 mg, 0.260 mmol) was added 1,4-dioxane (2 mL) and saturated NaHCO3 solution (1 mL) in a 5 mL vial. with airtight seal. Then, the mixture was bubbled with N 2 gas for 5 minutes. Pd (Ph3P) 4 (2.47 mg, 0.019 mmol) was added and the vessel was capped and heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 3 ml of DIVISO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minute experiment (47 ml / min, ACN / 20% H2O, 0.1% TFA to ACN / 45% H2O, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were washed in combination with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. The material was transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to give 7- (3-oxethanyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl] .) -2,3-dihydro-H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (46 mg, 50.2% yield) as a solid White. LC-MS (ES) m / z = 494.4 [+ H] +. 1 H NMR (400 MHz, DMSO-de) d 8.1-1.8.17 (m, 2H), 7.67-7.72 (m, 2H), 7.56-7.67 (m, 3H) , 7.40 (s, 1 H), 7.29 (d, J = 8.08 Hz, 1 H), 6.16 (broad s, 2H), 5.88 (quin, J = 7.14 Hz) , 1 H), 4.95 - 5.04 (m, 4H), 4.28 (t, J = 8.34 Hz, 2H), 4.04 (s, 2H), 3.27 (t, J = 8.34 Hz, 2H).

EXAMPLE 127 7-r2- (4-morpholminetin-5- (1-r3- (trifluoromethyl-U-indacetyl-V2.3-dihydro-1H-indol-5-yl) -7H-pyrrolor-2,3-c-pyrimidin-4-amine To 5-bromo-7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (50 mg, 0.153 mmol) and 5- (4.4 , 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (93 mg, 0.215 mmol) were added 1,4-dioxane (2 mL) and saturated NaHCO 3 solution (1 mL) in a 5 mL container with airtight seal. The mixture was then bubbled with N2 gas for 5 minutes, then Pd (Ph3P) 4 (17.71 mg, 0.015 mmol) was added and the reaction was capped and heated at 100 ° C overnight. After the reaction was diluted with water (2 ml) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minute experiment (47 ml / min, ACN / 18% H2O, 0.1% TFA to 43% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO 3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. The product was then transferred to a 40 ml vial with MeCN, then water was added and lyophilized to give 7- [2- (4-morpholinyl) ethyl] -5- (1 -. {3- [trifluoromethyl] ) phenyl] acetyl.} -2,3-dihydro-1 H-in pyrrolo [2,3-d] pyrimidin-4-amine (35 mg, 41.5% yield) as a white solid. LC-MS (ES) m / z = 551, 5 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.10-8.15 (m, 2H), 7.69 (s, 1 H), 7.56-7.66 (m, 3H), 7.33. (s, 2H), 7.24 (d, J = 8.34 Hz, 1 H), 6.06 (broad s, 2H), 4.24-4.31 (m, 4H), 4.04 ( s, 2H), 3.54 (broad s, 4H), 3.22-3.99 (m, J = 7.83 Hz, 2H), 2.71 (broad s, 2H), 2.46 (s) width, 4H).EXAMPLE 128 7- (1-methyl-ethyl) -5- (1 - (r3- (trifluoromethyl) phenylacetyl) -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolor-2,3-c / l-pyrimidin-4- amine To 5-bromo-7- (1-methylethyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (70 mg, 0.274 mmol) and 5- (4,4,5,5-tetramethyl) 1, 3,2-dioxaborolan-2-yl) -1 -. { [3- (Trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indole (166 mg, 0.384 mmol), 1,4-dioxane (2 mL) and saturated NaHCO 3 solution (1 mL) were added in a 5 mL container with airtight seal. . After the mixture was bubbled with N2 gas for 5 minutes, then Pd (Ph3P) (317 mg, 0.274 mmol) was added and the vessel was capped. The reaction mixture was then heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: Gilson open access using the Trilution software with a Sunfire 5u C18 (2) 100A 50x30.00 mm 5 micron column, experiment of 7 , 3 minutes (47 ml / min, ACN / 35% H2O, 0.1% TFA to ACN / 60% H2O, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume was reduced to separate the most of the MeCN. To the remaining water, saturated NaHCO 3 solution was added and the mixture was extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to provide 7- (1-methylethyl) -5- (1- {[[3- (thluoromethyl) phenyl] acetyl] .) -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (62 mg, 47.1% yield) in the form of a solid white. LC-MS (ES) m / z = 480.5 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d 8.23 (s, 1 H), 8, 13 (d, J = 8.34 Hz, 1 H), 7.69 (s, 1 H), 7, 57 -7.67 (m, 3H), 7.54 (s, 1 H), 7.36 (s, 1 H), 7.26 (d, J = 8.08 Hz, 1 H), 6, 57 (broad s, 2H), 4.99 (quin, J = 6.76 Hz, 1 H), 4.28 (t, J = 8.46 Hz, 2H), 4.04 (s, 2H), 3.23 - 3.28 (m, 2H), 1.47 (d, J = 6.82 Hz, 6H).

EXAMPLE 129 7- (3-methylbutyl) -5- (1-ir3-ftrifluoromethyl) phenynacetyl) -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolor-2-d1-pyrimidin-4-amine To 5-bromo-7- (3-methylbutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (75 mg, 0.265 mmol) and 5- (4,4,5,5-tetramethyl) l-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (160 mg, 0.371 mmol) were added 1,4-dioxane (2 mL) and saturated NaHCO 3 solution (1 mL) in a 5 mL container with airtight seal. The mixture was then bubbled with N2 gas for 5 minutes, then Pd (Ph3P) 4 (30.6 mg, 0.026 mmol) was added and the vessel was capped. The reaction mixture was then heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 3 ml of DMSO and the product was purified by HPLC: (HPLC conditions: Gilson using Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7, 3 minutes (47 ml / min, ACN / 40% H2O, 0.1% TFA to ACN / 65% H2O, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO 3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. The material was transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to provide 7- (3-methylbutyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl] .) -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (67 mg, 0.132 mmol, 49.8% yield) in shape of a white solid. LC-MS (ES) m / z = 508.5 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.15 (s, 1 H), 8.1 1 (d, J = 8.34 Hz, 1 H), 7.69 (s, 1 H), 7.56-7.66 (m, 3H). 7.33 (s, 2H), 7.24 (d, J = 8.34 Hz, 1 H), 6.10 (s broad, 2H), 4.27 (t, J = 8.46 Hz, 2H ), 4.18 (t, J = 7.33 Hz, 2H), 4.03 (s, 2H), 3.26 (t, J = 8.34 Hz, 2H), 1.69 (q, J) = 6.99 Hz, 2H), 1.50 (dt, J = 6.69, 13.39 Hz, 1 H), 0.93 (d, J = 6.57 Hz, 6H).

EXAMPLE 130 4-f1-r (3-methylphenyl) acetin-2,3-dihydro-1H-indol-5-ylMH-pyrazolor3,4-clpyridin-3-amine 3-chloro-5-. { 1 -! (3-methylene) acetyl-2,3-dM ' pyridinecarbonitrile A mixture of 3,5-dichloro-4-pyridinecarbonitrile (400 mg, 2.312 mmol), 1 - [(3-methylphenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole (872 mg, 2.312 mmol), Pd2 (dba) 3 (42.3 mg, 0.046 mmol) and K3P04 (982 mg, 4.62 mmol) in 9 ml of dioxane and 3 ml of water in a microwave tube was degassed and flushed with nitrogen, followed by the addition of the tri- (t-butyl) phosphonium tetrafluoroborate salt (26). , 8 mg, 0.092 mmol). The mixture was degassed and flushed with nitrogen. The mixture was heated in a microwave reactor at 120 ° C for 40 minutes.

The LCMS analysis showed that there was no starting material. The mixture was cooled to room temperature, and the mixture was filtered. The filtered solid was purified by silica gel column chromatography on a silica gel cartridge using elution with gradient of 100% CH 2 Cl 2 to CH 2 Cl 2 / CH 3 OH / NH 3 OH 90: 10: 1. The combined product fractions were evaporated to dryness to give 3-chloro-5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -4-pyridinecarbonitrile as a pale yellow solid (255 mg, 26% yield). LCMS [M + 1] 388. 1 H NMR (400 MHz, DMSO-d 6) d 2.31 (s, 3 H), 3.24 (t, J = 8.34 Hz, 2 H), 3.85 ( s, 2 H), 4.25 (t, J = 8.46 Hz, 2 H), 7.06-7.14 (m, 3 H), 7.20-7.27 (m, 1 H) , 7.51 (d, J = 8.34, 1 H), 7.58 (s, 1 H), 8.21 (d, J = 8.34 Hz, 1 H), 8.82 (s, 1 H), 8.93 (s, 1 H). 4- (1-r (3-methylphenyl) acetill-2,3-dihydro-1 H-indol-5-yl.} - 1 H-pyrazoloyl-3,4-clpyridin-3-amine To 3-chloro-5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -4-pyridinecarbonitrile (100 mg, 0.258 mmol) in ethanol (6 ml) was added hydrazine monohydrate (1 ml, 31.9 mmol), and the reaction mixture was stirred at 80 ° C overnight in a closed vessel. hermetically. The LCMS analysis of the reaction mixture indicated the presence of starting material. Therefore, the reaction mixture was stirred at 100 ° C overnight. The mixture was poured EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO 4), filtered and concentrated. The resulting residue was purified by flash chromatography on S1O2 (gradient: 100% hexanes to 100% EtOAc to CH3OH / 20% EtOAc). The fractions containing the product were combined, concentrated and triturated with Et20 to provide 4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} -1 - / - pyrazolo [3,4-c] pyridin-3-amine (15 mg) as a yellow solid. RN 1 H (400 MHz, DMSO-de) d 2.32 (s, 3 H), 3.25 (t, J = 8.34 Hz, 2 H), 3.85 (s, 2 H), 4, 24 (t, J = 8.46 Hz, 2 H), 4.6 (m, 1, 3H (NH2)), 7.05-7.16 (m, 3 H), 7.19-7.28 (m, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.42 (s, 1 H), 7.93 (s, 1 H), 8.21 (d, J = 8.34 Hz, 1 H), 8.74 (s, 1 H), 12.27 (broad s, 1 H).

EXAMPLE 131 7 parrot-3- (1-r (2,5-difluorophenyl) acetin-2,3-dihydro-1H-indol-5-yl.} Furor3.2-clpyridin-4-amine 5- (4-amnofurof3.2-clpiridin-3-yl) -2, 3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester 3-Bromofuro [3,2-c] pyridin-4-amine (7.23 g, 33.9 mmol), 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2) -yl) -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (12.90 g, 37.4 mmol), adduct of PdCl2 (dppf) -CH2Cl2 (1.39 g, 1.702 mmol), 1,4-dioxane (300 ml), and saturated aqueous solution of Sodium bicarbonate (100 ml, 100 mmol) was added to a 1 liter 3-neck flask equipped with a reflux condenser and a heating mantle. The flask was evacuated and filled with nitrogen 4 times, and then the mixture was stirred under reflux under a nitrogen atmosphere for 2 h. HPLC analysis showed complete conversion, so it was cooled and allowed to stir at room temperature overnight. The crude mixture was then filtered through Celite, rinsing with EtOAc (500 mL). The filtrate was washed with half-saturated aqueous NaHCO3 solution (500 ml), and the aqueous phase was back extracted with ethyl acetate (1 × 500 ml). The combined organic phases were washed with brine (1x500 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 600 g of Si02, gradient of EtOAc in hexanes at 20% -100% over 60 minutes, and then 100% EtOAc for an additional 30 minutes). The product fractions were combined and concentrated in vacuo to give 5- (4-aminofuro [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indole-1-carboxylate of 1 , 1-dimethylethyl (9.23 g, 26.3 mmol, 77% yield) as an off-white solid. LC / MS (ES) m / z = 352 [M + H] +. 5- (4-amino-7-vodofuroy3,2-clDiridin-3-yl) -2-dihydro-1-carboxylic acid 1,1-dimethylethyl ester A solution of NIS (0.985 g, 4.38 mmol) in DMF (20 mL) was added dropwise to a solution of 5- (4-aminofuro [3,2-c] pyridin-3-yl) -2, 3,1-Dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (1.505 g, 4.28 mmol) in DMF (20 mL) at -40 ° C under a nitrogen atmosphere. The mixture was stirred and allowed to warm slowly to room temperature for 17 hours. The LCMS analysis indicated approximately 85% conversion, whereby the mixture was cooled to about -30 ° C and another portion of NIS (0.193 g, 0.858 mmol) in DMF (3 mL) was added dropwise. It was then allowed to warm slowly to room temperature and stirred for another 24 hours. Then the reaction mixture was poured into water (approximately 200 ml) and the precipitate was collected by vacuum filtration and rinsed with 20 ml (50 ml) to give the 5- (4-amino-7-iodophide [3, 2-c] pyridin-3-yl) -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (2.384 g, 4.00 mmol, 93% yield) in the form of a brown solid. LC / MS (ES) m / z = 478 [M + H] +. 5- [4- (bis { [(1,1-dimethylethyl) oxylcarbonyl}. Amino) -7-vodofuro [3,2- c] pyridin-3-ill-2,3-dihydro-1 H- 1, 1 -dimethylethyl indole-1-carboxylate A mixture of 5- (4-amino-7-iodofuro [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (2.043 g , 4.28 mmol), Boc20 (6.95 mL, 29.9 mmol), triethylamine (4.2 mL, 30.1 mmol), and DMAP (0.028 g, 0.229 mmol) in dichloromethane (DCM) (40 mL). ) was stirred at room temperature under nitrogen for 16 hours. The LCMS analysis showed only starting material, and there was visible water in the reaction mixture (the starting material must not be completely dried). The mixture was poured into saturated aqueous NaHCO 3 solution (50 ml) and extracted with methylene chloride (2~50 ml). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil. The residue was resubjected to the reaction conditions by adding a second portion of each of Boc20 (6.95 mL, 29.9 mmol), dichloromethane (DCM) (40 mL), triethylamine (4.2 mL, 30%). 1 mmol) and DMAP (0.028 g, 0.229 mmol). The reaction mixture was stirred at room temperature under nitrogen for 6.5 h and then concentrated in vacuo. The dark residue was purified by flash chromatography (Analogix, 120 g S1O2, gradient of EtOAc in hexanes 0% -20% over 60 minutes) to give 5- [4- (bis { [(1, 1-dimethylethyl) oxy] carbonyl.} Amino) -7-iodophene [3,2-c] pyridin-3-yl] -2,3-dihydro-1 H indol-1-carboxylate 1,1-dimethylethyl ( 1.44 g). The NMR analysis showed some EtOAc, whereby the solid was dissolved in dioxane and concentrated in vacuo to give the EtOAc-free product along with some dioxane. LC / MS (ES) m / z = 678 [M + H] +. 5- [4- (bis { [(1,1-dimethylethyl) oxycarbonyl}. Amino) -7-chlorofuro [3,2-clpyridin-3-ill-2,3-dihydro-1H-indole-1 -l, 1-dimethylethyl carboxylate and 5- [7-chloro-4- (. {I (1-dimethylethyl) oxy] carbonyl) amino) furoy3,2-c] pyridin-3-yl ^ 1, 1-dimethylethyl indole-1-carboxylate TBuLi (1.7M in pentane) (0.59 mL, 1.003 mmol) was added dropwise to a solution of 5- [4- (bis. {[[(1,1-dimethylethyl) oxy] carbonyl. .}. amino) -7-yodofuro [3,2-c] pyridin-3-yl] -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (307 mg, 0.453 mmol) in THF (7 mL) at -78 ° C under nitrogen atmosphere. The mixture was stirred at this temperature for 15 minutes, and then added drop by drop a solution of hexachloroethane (217 mg, 0.917 mmol) in THF (3 mL). The reaction was stirred and allowed to slowly warm from -78 ° C to room temperature for 16 hours. The mixture was then quenched with saturated NH 4 Cl solution (25 mL), and extracted with ethyl acetate (2 * 20 mL). The extracts were washed with brine (1 x 20 mL), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g of S1O2 [RediSep Gold column], gradient of EtOAc in hexanes at 0% -25% over 45 minutes). The second peak (the first large one) was collected to give 5- [4- (bis. {[[(1,1-dimethylethyl) oxy] carbonyl.} Amino) -7-chlorofur [3,2- c] pyridin-3-yl] -2,3-dihydro-1 H-indol-1-carboxylic acid 1,1-dimethylethyl ester (81 mg, 0. 138 mmol, 30.5% yield) in the form of an oil colorless. LC / MS (ES) m / z = 586, 588 [M + H] +. The third eluting peak was also collected and found to be 5- [7-chloro-4- (. {[[(1,1-dimethylethyl) oxy] carbonyl} amino) furo [3,2-c] ] pihdin-3-yl] -2,3-dihydro-1 H-indol-1-carboxylate 1,1-dimethylethyl ester (33 mg, 0.068 mmol, 14.99% yield), also in the form of a colorless oil . LC / MS (ES) m / z = 486, 488 [M + H] +. 7-chloro-3- (2,3-dihydro-1H-indol-5-yl) furoí3,2-clpiridin-4-am The products 5- [4- (bis. {[[(1, 1-dimethylethyl) oxy] carbonyl}. Amino) -7-chlorofuro [3,2-c] pyridin-3-yl] -2.3- 1, 1-dimethylethyl dihydro-1 H-indole-1-carboxylate (81 mg, 0.138 mmol) and 5- [7-chloro-4- ( { [(1,1-dimethylethyl) oxy] carbon L.}. Amino) furo [3,2-c] pyridin-3-yl] -2,3-dihydro-1 H-indole-1,1-dimethylethyl carboxylate (33 mg, 0.068 mmol) ( 0.206 mmol total) were combined in DCM and concentrated to a pale yellow oil. To this oil was added 1,4-dioxane (0.5 ml) and to the resulting solution was added HCl (4 M, dioxane) (2 ml, 8.00 mmol), and the reaction was stirred overnight at room temperature. . The reaction mixture was concentrated to provide crude 7-chloro-3- (2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (81.5 mg) , 0.227 mmol, 164% yield) as a beige solid. LC-MS (ES) m / z = 286 [M + H] +. 1 H NMR (400 MHz, DMSO-cie) d ppm 2.64 (t, J = 7.83 Hz, 2 H), 3.09 - 3.19 (m, 2 H), 6.83 (s, 2 H), 6.90 (s, 1 H), 7.32 (s, 1 H), 7.46 (s, 1 H). Note, NHs are not observed. 7-chloro-3-. { 1- (2, 5-difluorophenyl) acetyl-2,3-dihydro-1H-indol-5-H) furo [3.2-cyClidin-4-amine] A solution of 7-chloro-3- (2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (58.9 mg, 0.206 mmol), acid ( 2,5-difluorophenyl) acetic (35.5 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) and DIEA (0.036 mL, 0.206 mmol) in?,? - dimethylformamide (DMF) (3 mL) was stirred for one night at room temperature. The LCMS analysis at this time indicated a good conversion, whereby the reaction mixture was poured into water (10 ml) and stirred for 1 hour. The resulting precipitate was collected by filtration, dried in the pump for 1 hour, adsorbed on silica and purified by flash chromatography (MeOH in 0-10% EtOAc) to provide 7-chloro-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (67 mg, 73.9% yield) as a white solid. LC-MS (ES) m / z = 440, 442 [M + H] +. 1 H-NMR (400 MHz, DMSO-cfe) d ppm 3.29 (t, J = 8.46 Hz, 2 H), 3.96 (s, 2 H), 4.31 (t, J = 8.34 Hz, 2 H), 5.72 (s, 2 H), 7.13 -7.34 (m, 4 H), 7.41 (s, 1 H), 7.92 (s, 1 H), 8.07 (s, 1 H), 8.13 (d, .7 = 8.34 Hz, 1 H).

EXAMPLE 132 7- (3-azetidinin-5- (1- (r3- (trifluoromethyl-phenylacetyl) -2,3-dihydro-1H-indol-5-yl) -7H-pyrrolor-2,3-cnpyrimidin-4-amine To the 1,1-dimethylethyl 3- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) -1-azetidinecarboxylate (70 mg, 0.190 mmol) and 5- (4 , 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (1 15 mg, 0.266 mmol) was added 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (1 ml) in a 5 ml vial with airtight seal. The mixture was then bubbled with N2 gas for 5 minutes, and then Pd (Phi3P) 4 (21.97 mg, 0.019 mmol) was added and the vessel was capped. The reaction mixture was then heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL).

Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 3 mL of DMSO and the product was purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7, 3 minutes (47 ml / min, 35% ACN / H20, 0.1% TFA to 60% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was added to saturated NaHCO3 solution and then extracted with EtOAc (3x15 mL). The organic extracts were washed combined with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was then transferred to a 40 ml vial with MeCN. Water was added and the solution was lyophilized. Then, 3 ml of a previously mixed DCM: TFA 2: 1 solution was added to the white solid obtained and allowed to stir for 30 min. The reaction was then concentrated and then dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: open access Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A 50x30 column., 00 mm 5 micrometers, 7.3 min experiment (47 ml / min, 5% ACN / H20, 0.1% TFA at 30% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was then passed through a column of 0.9 mmol Stratopheres SPE PL-HC03 MP SPE and then filtered and lyophilized to isolate 7- (3-azetidinyl) -5- (1 - { [3 - (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (48 mg, 41.6%) of performance) in the form of a white solid. LC / MS (ES) m / z = 493.5 [M + H] +.

EXAMPLE 133 7- (1-methyl-3-azetidinyl) -5- (1- (r3- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1 H- indol-5-yl) -7H-p rrolor2,3-o1pyrimidin-4-amine To 5-bromo-7- (1-methylethyl-3-azetidinyl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (64 mg, 0.227 mmol) and 5- (4,4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (Trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (137 mg, 0.318 mmol) was added 1,4-dioxane (2 mL) and saturated NaHCO 3 solution (1 mL) in a 5 mL container with airtight seal. The mixture was then bubbled with N2 gas for 5 minutes and then Pd (Ph3P) 4 (26.2 mg, 0.023 mmol) was added and the vessel was capped. The reaction mixture was then heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product then dissolved in 3 ml of DMSO and the was purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minute experiment (47 ml / min, ACN / 20% H2O, 0.1% TFA to 45% ACN / H2O, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. The product was then transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to provide 7- (1-methylbutyl-3-azetidinyl) -5- (1- {[3- ( trifluoromethyl) phenyl] acetyl.} -2,3-dih il) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (15 mg, 0.030 mmol, 13.06% yield) as a white solid. LC / MS (ES) m / z = 507.5 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.16 (s, 1 H), 8.14 (d, J = 8.08 Hz, 1 H), 7.69 (s, 1 H), 7, 57-7.67 (m, 4H), 7.38 (s, 1 H), 7.27 (d, J = 8.08 Hz, 1 H), 6.16 (s broad, 2H), 5, 41 (quin, J = 7.20 Hz, 1 H), 4.28 (t, J = 8.34 Hz, 2H), 4.06-4.13 (m, 2H), 4.04 (s, 2H), 3.90 - 3.99 (m, 2H), 3.24 - 3.29 (m, 2H), 2.65 (broad s, 3H).

EXAMPLE 134 7-r2- (dimethylamino) etn-5- (1-fr3 - (^ indol-5-yl) -7H-pyrrolor213-c lpyrimidin-4-amine To 5-bromo-7- [2- (dimethylamino) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine (67 mg, 0.236 mmol) and 5- (4,4,5,5 -tetramethyl-1, 3,2-d-oxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (142 mg, 0.330 mmol) was added 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (ml) in a 5 ml container with airtight seal. The mixture was then bubbled with N2 gas for 5 minutes, then Pd (Ph3P) 4 (27.2 mg, 0.024 mmol) was added and the vessel was capped. The reaction mixture was then heated at 100 ° C overnight. The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 micrometer, 7.3 minute experiment (47 ml / min, ACN / 15% H 2 O, 0.1% TFA to ACN / 35% H 2 O, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume was reduced and lyophilized. The QC analysis of the sample detected some impurities. The lyophilized product was dissolved in DMSO (2.5 ml) and purified again by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7.3 minutes (47 ml / min, ACN / 15% H2O, 0.1% TFA to 35% ACN / H2O, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated. The product was transferred to a 40 ml vial with MeCN, water was added and the solution was lyophilized to give 7- [2- (dimethylamino) ethyl] -5- (1 - { [3- (trifluoromethyl) phenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (18 mg). LC / MS (ES) m / z = 509.5 [M + H] +. 1 H-NMR (400 MHz, DMSO-d 6) d 8, 14 (s, 1 H), 8, 12 (d, J = 8.59 Hz, 1 H), 7.69 (s, 1 H), 7, 58 -7.67 (m, 3H), 7.33 (s, 2H), 7.24 (d, J = 8.59 Hz, 1 H), 6.05 (broad s, 2H), 4.24 -4.31 (m, 4H), 4.04 (s, 2H), 3.27 (t, J = 8.59 Hz, 2H), 2.70 (broad s, 2H), 2.22 (s) width, 6H).

EXAMPLE 135 5- (4-Fluoro-1- (trifluoromethyl) phenyl-1-acetyl) -2,3-dihydro-1H-indol-5-yn-7-methyl-7H-pyrroloyl-2,3-cnpyrimidin-4-amine To a suspension of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidine-4-a dihydrochloride. Na (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (314 ul, 1.80 mmol , 3.2 equiv) in a single portion. To this mixture was added [3- (trifluoromethyl) phenyl] acetic acid in portions (15 mg total, 0.56 mmol, 1 equiv) over a period of 1 h. After a total of 1.5 hours, the LCMS analysis showed complete conversion. The mixture was poured into 20 ml of ice-cooled water to give a suspension which was filtered. The filter cake was washed with water and dried with a laboratory vacuum system. The solid residue was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. The purification was done in a silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHCI3 at A in 60% CHCI3 (A was a mixture of CHCI3 / MeOH / NH4OH 3200/800/80, gradient: 0-5 min: A at 1%, 5-35 min A at 5-60%). The desired product eluted in A at 27-32%. The combined fractions were concentrated in vacuo to give the product, which the LCMS analysis showed was only 89% pure. The sample was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. The purification was done in a silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc to 100% A (A was a mixture of MeOH in 10% EtOAc). The desired product eluted in A at 67-87%. The combined fractions were concentrated in vacuo. The residue was dissolved in 10 mL of MeOH in 10% DCM and concentrated in vacuo to a suspension (approximately 2 mL). This mixture was diluted with 12 ml of MTBE. The resulting suspension was filtered. The filter cake was washed with MTBE (3x 4 mL) and hexane (3x 4 mL), and dried under vacuum at 65 ° C for 18 h to provide the 5- (4-fluoro-1- {. [3. - (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 / - / - indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (182 mg) as a white solid. LC-MS (ES) m / z = 470 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.28 (t, J = 8.1 Hz, 2 H), 3.74 (s, 3 H), 4.04 (s, 2 H), 4 , 34 (t, J = 8.3 Hz, 2 H), 5.88 - 6.16 (broad s, 1.6 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.54-7.73 (m, 4 H), 7.92 (d, J = 8.3 Hz, 1 H), 8.14 (s, 1 H) .

EXAMPLE 136 5-. { 4-fluoro-1 - [(6-methy1-2-pyridyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3- /] pyrimidin-4-amine To a suspension of 5- (4-fluoro-2,3-dihydro-1 H -indole-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride ( 200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (412 ul, 2.36 mmol, 4, 2 equiv) in a single portion. To this mixture was added the (6-methyl-2-pyridinyl) acetic acid TFA salt (148 mg) in portions over a period of 1 h. After a total of 2 h, the LCMS analysis showed complete conversion. The mixture was poured into 20 ml of ice-cooled water to give a suspension which was filtered. The filter cake was washed with water and dried with a laboratory vacuum system to provide the crude product, which was dissolved in 10% DCM in eOH and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHCl3 at A in 60% CHCI3 (A was a mixture of CHCI3 / MeOH / NH4OH 3200/800/80 , gradient: 0-5 min: A at 1%, 5-35 min A at 5-60%). The desired product eluted in A at 27-34%. The combined fractions were concentrated in vacuo. The residue was dissolved in MeOH in DCM to 10% and absorbed in a dry charge cartridge. Purification was done on a silica gel cartridge of Analogix SF25-60 g using gradient elution of A in 1% EtOAc at 100% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 83-100%. The combined fractions were concentrated in vacuo. The residue was dissolved in 12 mL of MeOH in 10% DCM and concentrated in vacuo to a suspension (approximately 2 mL). This mixture was diluted with 12 ml of MTBE. The resulting suspension was concentrated in vacuo to reduce to half the volume. The mixture was diluted with another 10 ml of MTBE. The suspension was filtered. The filter cake was washed with MTBE (2x 4 ml) and hexane (3x 4 ml), and dried under vacuum at 65 ° C for 18 h to provide the 5-. { 4-Fluoro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3 - (^ pyrimidin-4-amine (123 mg) as a white solid LC-MS (ES) m / z = 417 [M + H] +. (400 MHz, DMSO-d6) d ppm 2.45 (s, 3H), 3.25 (t, J = 8.5 Hz, 2 H), 3.74 (s, 3 H), 4.00 ( s, 2 H), 4.35 (t, J = 8.5 Hz, 2 H), 5.90 - 6.17 (broad s, 1.6 H), 7, 12 - 7.23 (m, 3 H) ), 7.27 (s, 1 H), 7.66 (t, J = 7.7 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1 H), 8, 14 ( s, 1 H). (ES) m / z = 417 [M + H] +.

EXAMPLE 137 5 4-fluoro-1 - (r6- (trifluoromethyl-2-pyridinillacetyl) -2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolor-2,3-dlpyrimidin-4-amine To a suspension of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pinmidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (412 ul, 2.36 mmol, 4.2 equiv) in a single portion. To this mixture was added [6- (trifluoromethyl) -2-pyridinyl] acetic acid (179 mg) in portions over a period of 1 hour. After an additional 30 minutes, the LCMS analysis showed complete conversion. The mixture was poured into 20 ml of ice-cooled water to give a suspension which was filtered. The filter cake was washed with water and dried with a laboratory vacuum system to give the crude product, which was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHCl3 at A in 65% CHCI3 (A was a mixture of CHCI3 / MeOH / NH4OH 3200/800/80 , gradient: 0-5 min: A 1%, 5-35 min A 5-60%). The product eluted around A at 26-31%. The fractions combined with product were concentrated in vacuo. The residue dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc at 75% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 51 -70%. The combined fractions were concentrated in vacuo. The residue was dissolved in 12 mL of MeOH in 10% DCM and concentrated in vacuo to a suspension (approximately 1 mL). This mixture was diluted with 12 ml of MTBE. The resulting suspension was concentrated in vacuo to reduce to half the volume. The mixture was diluted with another 10 ml of MTBE. The suspension was filtered. The filter cake was washed with MTBE (2x 4 mL) and hexane (3x 4 mL), and dried under vacuum at 65 ° C for 18 h to provide the 5- (4-fluoro-1 -. - (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H-indol-5-yl ^ 7H-pyrrolo [2,3-d] pyrimidin-4-amino (205 mg) as a white solid. LC-MS (ES) m / z = 471 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.28 (t, J = 8.5 Hz, 2 H), 3.74 (s, 3 H), 4.22 (s, 2 H), 4 , 38 (t, J = 8.6 Hz, 2 H), 5.90 - 6.19 (broad s, 1.5 H), 7.20 (t, J = 8.1 Hz, 1 H), 7.28 (s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 8.10 (t, 7.8 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 138 5- (1-r (3,5-dimethyl-1-pyrazol-1-yl) acetyl ^ 7-methyl-7H-pyrrolof2,3-cnpyrimidin-4-amine To a suspension of 5- (4-fluoro-2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pihydrochloride. rimidin-4-amino (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA ( 314 ul, 1.80 mmol, 3.2 equiv) in a single portion. To this mixture was added (3,5-dimethyl-1 H-pyrazol-1-yl) acetic acid (87 mg, 0.56 mmol, 1 equiv) in portions over a period of 1 h. After another 30 min, the LCMS analysis showed that there was still 27% starting amine. To the mixture was added 18 mg of (3,5-dimethyl-1 H-pyrazol-1-yl) acetic acid. After 1 hour, the mixture was poured into 20 ml of ice water to give a suspension which was filtered. The filter cake was washed with water and dried with a laboratory vacuum system to provide the crude product, which was dissolved in 10% DCM in eOH and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHC at A in 65% CHCl3 (A was a mixture of CHCl3 / MeOH / NH4OH 3200/800/80 , gradient: 0-5 min: A 1%, 5-35 min A 5-60%). There were impurities that They moved nearby (moved with the front) with slightly less retention time. The desired product eluted in A at 29-35%. The combined fractions were concentrated in vacuo. The residue was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc at 100% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 90-100%. Again, there was a non-polar impurity with a slightly lower retention time. The combined fractions were concentrated in vacuo. The residue was dissolved in 12 ml of MeOH in 10% DCM and concentrated in vacuo. The wet residue was diluted with 12 ml of MTBE. The resulting suspension was concentrated in vacuo to reduce to half the volume. The mixture was diluted with another 6 ml of MTBE. The suspension was filtered. The filter cake was washed with MTBE (2x 4 mL) and hexane (3x 4 mL), and dried under vacuum at 65 ° C for 18 h to provide the 5-. { 1 - [(3,5-dimethyl-1 / - / - pyrazol-1-yl) acetyl] -4-fluoro-2,3-dihydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-c] pyrimidin-4-amine (98 mg) as a white solid. LC-MS (ES) m / z = 420 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.10 (s, 3 H), 2.16 (s, 3 H), 3.29 (t, J = 8.3 Hz, 2 H), 3 , 74 (s, 3 H), 4.34 (t, J = 8.3 Hz, 2 H), 5.1 1 (s, 2 H), 5.86 (s, 1 H), 5.93 - 6.17 (broad s, 1.5 H), 7.21 (t, J = 8.1 Hz, 1 H), 7.28 (s, 1 H), 7.87 (d, J = 8) , 1 Hz, 1 H), 8, 14 (s, 1 H).

EXAMPLE 139 5- (4-fluoro-1- (4-fluoro-3- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1H-indol-5-yl) -7-methyl-7H-pyrrolof2,3-c1pyrimidin-4 -amine To a suspension of 5- (4-fluoro-2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimide dihydrochloride d-n-4-amino (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA ( 314 ul, 1.80 mmol, 3.2 equiv) in a single portion. To this mixture was added [4-fluoro-3- (trifluoromethyl) phenyl] acetic acid in portions (125 mg total, 0.56 mmol, 1 equiv) over a period of 1 h. After an additional 1 hour, the mixture was poured into 20 ml of ice water to give a suspension, which was filtered. The filter cake was washed with water and dried with a laboratory vacuum system to provide the crude product, which was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHCl3 at A in 65% CHCI3 (A was a mixture of CHCI3 / MeOH / NH4OH 3200/800/80 , gradient: 0-5 min: A 1%, 5-35 min A 5-60%). The desired product eluted in A at 30-36%. The combined fractions were concentrated in vacuo. The residue was dissolved in MeOH in 10% DCM and absorbed in a loading cartridge in dry. Purification was done on an Analogix silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc at 75% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 34-64%. The combined fractions were concentrated in vacuo. The residue was dissolved in 20 ml of MeOH in 10% DCM and concentrated in vacuo. The volume was reduced to approximately 4 ml, and the mixture was diluted with 10 ml of MTBE. The resulting suspension was concentrated in vacuo to a wet paste which was diluted with another 10 ml of MTBE. The suspension was filtered. The filter cake was washed with MTBE (3 x 4 mL) and dried under vacuum at 65 ° C for 18 h to provide 5- (4-fluoro-1- {. [4-fluoro-3- (trifluoromethyl) ) phenyl] acetyl] -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (181 mg) in white solid form. LC-MS (ES) m / z = 488 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.28 (s, J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 4.03 (s, 2 H), 4 , 34 (t, J = 8.3 Hz, 2 H), 5.87 - 6.19 (broad s, 1.6 H), 7.20 (t, J = 8.0 Hz, 1 H), 7.27 (s, 1 H), 7.45-7.55 (m, 1 H), 7.63-7.70 (m, 1 H), 7.73 (d, J = 7.1 Hz , 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 140 3- (1-r (2,5-difluorophenyl) acetm- ^ clpyridin-4-amine 5- (4-amnofuro [3,2-c] pyridin-3-yl) -4-fluoro-2,3-dihydro-1 H-indol-1-carboxylate 1,1-d-methylethyl ester 3-Bromofuro [3,2-c] pyridin-4-amino (310 mg, 1, 455 mmol), 4-fluoro-5- (4,4,5l5-tetramethyl-1, 3,2-d) Oxaborolan-2-yl) -2,3-dithyro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (577 mg, 1.589 mmol), adduct of PdCl2 (dppf) -CH2CI2 (65 mg, 0.080 mmol), 1,4-dioxane (15 ml), and saturated aqueous sodium bicarbonate solution (4.5 ml, 4.50 mmol) were added to a 200 ml flask equipped with a 200 ml flask coolant. Reflux. The flask was evacuated and filled with nitrogen 4 times, and then the mixture was stirred at 100 ° C under nitrogen for 15 hours. The LCMS analysis showed complete and clean conversion, so it was cooled and filtered through Celite, rinsing with EtOAc (50 ml). The filtrate was washed with semi-saturated aqueous solution of NaHCC > 3 (50 mL), and the aqueous phase was back extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with brine (1 x 100 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 60 g of SiO, gradient of EtOAc in hexanes at 10% -75% over 60 minutes) to give 5- (4-aminofuro [3,2-c]). ] pyridin-3-yl) -4-fluoro-2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (205 mg, 0.555 mmol, 38.1% yield) in the form of a whitish solid. LC / MS (ES) m / z = 370 [M + H] +. 3- (4-fluoro-2, 3-dihydro-1 H-indol-5-H) furo [3, 2-c] pyridin-4-amine A mixture of 5- (4-aminofuro [3,2-c] pyridin-3-yl) -4-fluoro-2,3-dihydro-1 H-indole-1-carboxylate 1,1-dimethylethyl ester (205 mg, 0.555 mmol) and HCl, 4.0 M in dioxane (2775 μl, 11.1 mmol) was stirred at room temperature under nitrogen for 16 h. Then, the reaction mixture was concentrated in vacuo to give 3- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (226 mg, 0.555 mmol, 100% yield), as an off-white solid. LC / MS (ES) m / z = 270 [M + H] +. 3- ^^ 2,5 - ^^? G? ^ ?? / 7) 8 ??? / - 4 - ^? G? -2.3- ^ 7 ^? - ^? - /? € /? / - 5 - \\) iuro \ 22-c] D \ rd \ n-4-an) \ na A mixture of 3- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) furo [3,2-c] pyridin-4-amine (190 mg, 0.555 mmol), acid 2.5 -difluorophenylacetic acid (100 mg, 0.583 mmol), HATU (232 mg, 0.61 1 mmol), and Hunig's base (0.388 mL, 2.221 mmol) in?,? - dimethylformamide (DMF) (5 mL) was stirred at room temperature. environment for 2 hours. HPLC analysis indicated complete consumption of the starting material, whereby the mixture was poured into water (30 ml), the suspension was stirred for a few minutes, and the precipitate was collected by vacuum filtration and dried in the vacuum oven overnight to give the 3- . { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pindin-4-amine (209 mg, 0.469 mmol, 84% yield) as a light brown solid. LC / MS (ES) m / z = 424 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 3.26-3.31 (d, J = 8.34 Hz, 2 H), 3.97 (s, 3 H), 4.38 (t, J = 8.46 Hz, 2 H), 5.48 (s, 2 H), 6.95 (d, J = 5.81 Hz, 1 H), 7.14 - 7.35 (m, 4 H), 7.87 (d, J = 6.06 Hz, 1 H), 7.93 (d, J = 8.08 Hz, 1 H), 7.96 (s, 1 H).

EXAMPLE 141 5- (4-fluoro-1-r (4-fluorophenyl) acetin-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolor-2,3-cnpyrimidin-4-amine To a suspension of 5- (4-fluoro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine dihydrochloride. (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (314 ul, 1.80 mmol, 3 , 2 equiv) in a single portion. To this mixture was added (4-fluorophenyl) acetic acid in portions (97 mg total, 0.56 mmol, 1 equiv) over a period of 1 h. After an additional 1 hour, the mixture was poured into 20 ml of ice water to give a suspension, which was filtered. The filter cake was washed with water and dried with Vacuum laboratory system to provide the gross product. This material was dissolved in MeOH in 10% DCM and adsorbed on a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-40 g using elution with gradient of A in 1% CHCl3 at A in 65% CHCI3 (A was a mixture of CHCI3 / MeOH / NH4OH 3200/800/80 , gradient: 0-5 min: A 1%, 5-35 min A 5-60%). The desired product eluted in A at 28-32%. The combined fractions were concentrated in vacuo. The residue was dissolved in MeOH in 10% DCM and absorbed in a dry loading cartridge. Purification was done on an Analogix silica gel cartridge SF25-60 g using gradient elution of A in 1% EtOAc at 75% A (A was a mixture of MeOH in 20% EtOAc). The desired product eluted in A at 36-60% (as a broad peak). The combined fractions were concentrated in vacuo. The residue was dissolved in 20 ml of MeOH in 10% DCM and concentrated in vacuo. The volume was reduced to about 5 ml, and the mixture was diluted with 10 ml of MTBE. The resulting suspension was concentrated in vacuo to a wet paste which was diluted with another 10 ml of MTBE. The suspension was filtered. The filter cake was washed with MTBE (3 × 4 ml) and dried under vacuum at 65 ° C for 18 h to provide 5-. { 4-fluoro-1 - [(4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine (148 mg) as a white solid. LC-MS (ES) m / z = 420 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.25 (t, J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 4 , 30 (t, J = 8.3 Hz, 2 H), 5.89 - 6.17 (broad s, 1 h), 7.15 - 7.21 (m, 3 H), 7.26 (s) , 1 H), 7.32-7.35 (m, 2 H), 7.93 (d, J = 8.3 Hz, 1 H), 8.14 (s, 1 H).

EXAMPLE 142 4- (1 - (r3- (trifluoromethyl) phenynacetyl-2,3-dihydro-1H-indol-5-yl) -1H-pyrazolor3,4-c1pyridin-3-amine 3 parrot-5- (1- { F3- (trifluoromethyl) phenylacetyl) -2.3-dM ^ il) -4-pyridinecarbonitrile To 3,5-dichloro-4-pyridinecarbonitrile (300 mg, 1.74 mmol) and 5- (4,4,5) 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl dihydro-1 H-indole (823 mg, 1.908 mmol) in a 5 mL sealed vial was added 1,4-dioxane (5 mL) and saturated NaHCO 3 solution ( 2.5 mi). The mixture was then bubbled with N2 gas for 5 minutes and then Pd (Ph3P) 4 (200 mg, 0.173 mmol) was added. Then the vial was capped and heated at 100 ° C overnight. The reaction was then diluted with water (10 mL) and then extracted with EtOAc (3x20 mL). The organic extracts were combined and then washed with brine, dried over MgSO4, filtered and concentrated. The crude solid was then dissolved in 3 ml of DMF and loaded onto a 50 g Biotage SNAP column packed with hexane and purified by chromatography on silica gel with EtOAc in hexane gradient from 0 to 60% over 30 minutes. minutes The fractions with the desired product were mixed and concentrated. After the semi-solid oil is treated with 20 ml DCM / 5% hexane to induce precipitation. The solid was isolated by filtration to give 3-chloro-5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) - 4-pyridinecarbonitrile (421 mg, 54.9% yield) as a yellow solid. LC / MS (ES) m / z = 442.4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 5) d 8.94 (s, 1 H), 8.83 (s, 1 H), 8.18 (d, J = 8.34 Hz, 1 H), 7, 69 (s, 1 H), 7.56 - 7.67 (m, 3H), 7.51 (d, J = 8.08 Hz, 1 H), 4.31 (t, J = 8.59 Hz , 2H), 4.06 (s, 2H), 3.29 (t, 3H). 4- (1 - {3- (trifluoromethyl) phenylacetyl} -2.3-dihydro-1H-indol-5-yl) -1 H-Dirazolof3,4-clDiridin-3-amine To 3-chloro-5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -4-pyridinecarbonitrile (80 mg, 181 mmol) was added hydrazine monohydrate (0.266 mL, 5.43 mmol) in a 5 mL vial with an ethanol seal (3 mL). The reaction was then capped and heated at 100 ° C overnight. 80% of product and 20% of starting material were observed. Additional hydrazine monohydrate (0.266 ml, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated and then dissolved in 3 mL of DMSO and the was purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 minutes (47 ml / min, ACN / 17% H20, 0.1% TFA at 42% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the water that remained Saturated NaHCO 3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. After the residue was transferred to a 40 ml vial with MeCN, water was added and the solution was lyophilized to give 4- (1 - { [3- (trifluoromethyl!) Fentl] acetyl} -2.3 -dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4-c] pyridin-3-amine (20 mg, 25.3% yield) as a white solid. LC / MS (ES) m / z = 438.4 [M + H] +. 1 H-NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1 H), 8.74 (s, 1 H), 8.18 (d, J = 8.34 Hz, 1 H), 7.93 (s, 1 H), 7.69 (s, 1 H), 7.56 - 7.67 (m, 3H), 7.44 (s, 1 H), 7.33 (d, J = 8, 34 Hz, 1 H), 4.61 (broad s, 2H), 4.30 (t, J = 8.46 Hz, 2H), 4.05 (s, 2H), 3.26 - 3.30 ( m, 2H).

EXAMPLE 143 1 - . 1-methyl-4- (1 - (r3- (trifluoromethyl-phenylacetyl) -2,3-dihydro-1 H -indol-5-ylH-pyrazolor-3,4-c-pyridin-3-amine To 3-chloro-5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-H-indol-5-yl) -4-pyridinecarbonitrile (80 mg, 0.181 mmol ) methylhydrazine (0.286 mL, 5.43 mmol) was added in a 5 mL vial with an ethanol seal (3 mL). The reaction was then capped and heated at 100 ° C overnight. HE observed incomplete conversion. Additional methylhydrazine (0.286 ml, 5.43 mmol) was added and heating was continued overnight. The reaction was concentrated, dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 micrometer, experiment 7). , 3 minutes (47 ml / min, ACN / 17% H20, 0.1% TFA at 42% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO 3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The product was transferred to a 40 ml vial with MeCN, then water was added and the solution was lyophilized to give 1-methyl-4- (1 - { [3- (trifluoromethyl) phenyl] acetyl} - 2,3-dihydro-1 H-indol-5-yl) -1 H -pyrazolo [3,4-c] pyridin-3-amine (34 mg, 41.6% yield) as light yellow solid . LC / MS (ES) m / z = 452.5 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 8.88 (s, 1 H), 8.17 (d, J = 8.34 Hz, 1 H), 7.94 (s, 1 H), 7.69. (s, 1 H), 7.56-7.66 (m, 3H), 7.43 (s, 1 H), 7.32 (d, J = 8.08 Hz, 1 H), 4.67 (s broad, 2H), 4.30 (t, J = 8.46 Hz, 2H), 4.05 (s, 2H), 3.92 (s, 3H), 3.29 (t, 2H).

EXAMPLE 144 7- (3-azetidyl) -5-m (2,5-difluorophene) pyrrolor2.3-dlpyrimidin-4-amine To 3- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimid-7-yl) -1-azetidinecarboxylic acid 1,1-dimethylethyl ester (70 mg, 0.190 mmol) and 1 - [(2,5-difluorophenyl) acetyl] -5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,3-d Hydro-1 H-indole (106 mg, 0.266 mmol) was added 1,4-dioxane (2 ml) and saturated NaHCO 3 solution (1 ml) in a 5 ml container with airtight seal. The mixture was then bubbled with N 2 gas for 5 min, then Pd (Ph 3 P) 4 (21, 97 mg, 0.019 mmol) was added and the mixture was sealed and heated at 100 ° C overnight.

The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). Then the organic extracts were combined and washed with brine, dried over MgSO4, filtered and evaporated, then dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire column 5u C18 (2) 100A, 50x30.00 mm 5 micrometers, 7.3 minute experiment (47 ml / min, ACN / 35% H20, 0.1% TFA at 60% ACN / H2Q, TFA at 0.1%) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated aHC03 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was transferred to a 40 ml vial with MeCN, then water was added and the mixture was lyophilized to give a white solid. 3 ml of a solution of DCM: TFA 2: 1 previously mixed with the white solid was added, and the mixture was stirred for 30 minutes. The reaction was then concentrated and then dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, experiment 7.3 minutes (47 ml / min, 5% ACN / H20, 0.1% TFA at 30% ACN / H20, 0.1% TFA) with UV detection at 220 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was passed through a column of 0.9 mmol Stratopheres SPE PL-HC03 MP SPE and the filtrate was lyophilized to give 7- (3-azetidinyl) -5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine (47 mg) as a white solid. LC / MS (ES) m / z = 461, 4 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d 9.06 (broad s, 2H), 8.34 (s, 1 H), 8.13 (d, J = 8.34 Hz, 1 H), 7, 81 (s, 1 H), 7.38 (s, 1 H), 7, 15 - 7.31 (m, 4H), 5.70 (qd, J = 7.71, 7.96 Hz, 1 H ), 4.54 - 4.65 (m, 2H), 4.47 (broad s, 2H), 4.31 (t, J = 8.46 Hz, 2H), 3.97 (s, 2H), 3.29 (t, J = 8.46 Hz, 2H).

EXAMPLE 145 7-r2- (4-piperidinyl) etill-5- (1- (r3- (trifluoromethyl) phenylacetyl) -2.3-dihydro-1H-indol-5-yl) -7H-pyrrolor-2,3-d-pyrimidin-4-amine Al 4- [2- (4-amino-5-bromo-7H-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] -1-piperidinecarboxylate 1,1-dimethylethyl ester (80 mg, 0.189 mmol) and 5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1-. { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indole (114 mg, 0.264 mmol) was added 1,4-dioxane (2 mL) and saturated NaHCO 3 solution (1 mL) in a 5 mL container with airtight seal. The mixture was then bubbled with N 2 gas for 5 min, then Pd (Ph 3 P) 4 (21, 79 mg, 0.019 mmol) was added and the mixture was sealed and heated at 100 ° C overnight.

The reaction was then diluted with water (2 mL) and then extracted with EtOAc (3x3 mL). The organic extracts were then combined and washed with brine, dried over MgSO4, filtered and evaporated. The residue was dissolved in 3 ml of DMSO and purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a column Sunfire 5u C18 (2) 100A, 50x30.00 mm 5 micrometers, 7.3 min experiment (47 ml / min, ACN / 40% H20, 0.1% TFA at 65% ACN / H20, TFA at 0, 1%) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. To the remaining water, saturated NaHCO 3 solution was added and then the mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The residue was transferred to a 40 ml vial with MeCN, then water was added and the mixture was lyophilized to give a white solid.

To the white solid, 3 ml of a previously mixed DCM: TFA 2: 1 solution was added and the mixture was stirred for 30 minutes. The reaction was then concentrated and the residue was dissolved in 3 ml of DMSO and then purified by HPLC: (HPLC conditions: Gilson using the Trilution software with a Sunfire 5u C18 (2) 100A column, 50x30.00 mm 5 microns, 7.3 min experiment (47 ml / min, 5% ACN / H20, 0.1% TFA at 30% ACN / H20, 0.1% TFA) with UV detection at 254 nm). The product fractions were combined and the volume reduced to remove most of the MeCN. The remaining water was passed through a column of 0.9 mmol Stratopheres SPE PL-HC03 MP SPE and then the filtrate was lyophilized to isolate 7- [2- (4-piperidinyl) ethyl] -5- (1-. { . [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine (56 mg) in shape of a white solid. LC / MS (ES) m / z = 549.6 [M + H] +. 1 H NMR (400 MHz, DMSO- d6) d 8.52-8.58 (m, 1 H), 8.38-8.40 (m, 1 H), 8.23-8.30 (m, 1 H), 8, 15 (d , J = 8.34 Hz, 1 H), 7.68 (s, 1 H), 7.59-7.68 (m, 4H), 7.35 (s, 1 H), 7.27 (d) , J = 7.83 Hz, 1 H), 4.24 - 4.32 (m, 4H), 4.05 (s, 2H), 3.22 - 3.29 (m, 4H), 2.77 - 2.87 (m, J = 1 1, 87 Hz, 2H), 1, 86-1, 92 (m, 2H), 1.79 (q, J = 7.07 Hz, 2H), 1.48 (s broad, 1 H), 1, 26-1, 38 (m, 2H).

EXAMPLE 146 7- (2-aminoethyl) -3- (1-f (2,5-difluorophenyl) acetyl-fluoro-2,3-dihydro-1 H-indol-5-yl) furor3.2-c1pyridin-4-amine 3-. { 1-r (2,5-difluorophenyl) acetill-4-fluoro-2,3-dihid ^ vodofuroi3,2-clDiridin-4-amine A solution of NIS (130 mg, 0.578 mmol) in DMF (2 mL) was added dropwise to a solution of 3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (190 mg, 0.449 mmol) in DMF (2.5 ml) at -40 ° C, and the mixture was stirred and allowed to slowly warm to room temperature. It was stirred for 25 hours, then poured into water (25 ml) and stirred for a few minutes. The precipitate was collected by filtration with vacuum. Then the wet solid was rinsed in another flask with filter using DCM (50 ml), and the filtrate was dried (Na2SO4), filtered and concentrated in vacuo to give the 3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} -7-iodofuro [3,2-c] pyridin-4-amine (252 mg) as a dark solid. LC / MS (ES) m / z = 550 [M + H] +. (3-. {(2,5-difluomophenyl) a8till-4-fluom-2.3-d Bis (l-dimethylethyl) vodidopylamino3.2-cyDiridin-4-yl) v (. {5-G4- (bis. {[[(1,1-dimethylethyl) oxylcarbonylamino) -7-iodophide [3, 2 -ClDiridin-3-ill-4-fluoro-2, 3-dihydro-1 H-indol-1-dicarbonyl) (2,5-difluorophenyl) Drodanedioate of bs (1,1-dimethylethyl) A mixture of 3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} -7-iodofuro [3,2-c] pyridin-4-amine (252 mg, 0.459 mmol), Boc20 (700 mg, 3.21 mmol), triethylamine (0.45 mL, 3.25 mmol) and DMAP ( 5 mg, 0.041 mmol) in dichloromethane (DCM) (5 ml) was stirred at room temperature under nitrogen for 3 hours. The LCMS analysis indicated that there was no conversion, so another portion of Boc20 (770 mg, 3.53 mmol) was added and stirring was continued for a further 16 hours. The LCMS analysis still showed incomplete conversion (about 25% was still present), so a third portion of Boc20 (628 mg, 2.88 mmol) was added and stirring was continued for another 5 hours. The LCMS analysis showed almost complete conversion, so the mixture was concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 60 g Si02, gradient EtOAc in hexanes 0% -35% throughout 45 minutes) to give (3- {1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl}. Bis (1,1-dimethylethyl) iodofuro [3,2-c] pyridin-4-yl) imidodicarbonate (63 mg) in the form of a yellow film. It eluted another main peak and was also collected to give a tetra-Boc derivative, which was assigned as (. {5- [4- (bis. {[[(1,1-dimethylethyl) oxy] carbonyl} amino. ) -7-iodophuro [3,2-c] pyridin-3-yl] -4-fluoro-2,3-dihydro-1 H-indol-1-yl}. Carbonyl) (2,5-difluorophenyl) propanedioate of bis (1,1-dimethylethyl) (174 mg) by NMR. 7- (2-aminoethyl) -3-. { 1-r (2,5-d-fluoro-phenyl) -acetin-4-fluoro-2,3 1 H-indol-5-l} furof3, 2-clpyridin-4-amine A mixture of (3-. {1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl.} - 7-iodofide [3, 2-C] pyridin-4-yl) imidodicarbonate of bis (1,1-dimethylethyl) (63 mg, 0.084 mmol), (. {5- [4- (bis { [(1,1-dimethylethyl)) oxy] carbonyl.} amino) -7-yodofuro [3,2-c] pyridin-3-yl] -4-fluoro-2,3-dihydro-1 H-indol-1-yl.} carbonyl) ( Bis (1,1-dimethylethyl) 2,5-difluorophenyl) propanedioate (174 mg, 0.183 mmol), potassium tert-butyl-N- [2- (trifluoroboranuidyl) ethyl] carbamate (136 mg, 0.542 mmol) , palladium acetate (11) (6 mg, 0.027 mmol), RuPhos (25 mg, 0.054 mmol), and cesium carbonate (265 mg, 0.813 mmol) in toluene (3 mL) and water (1 mL) were degassed with nitrogen for 10 minutes. The 20 ml container was hermetically sealed and stirred vigorously at 95 ° C for 14 hours. It was cooled, diluted with ethyl acetate (15 mL), and washed with a half-saturated aqueous solution of NaHCO 3 (15 mL). The aqueous phase was back extracted with EtOAc (15 mL), and the combined organic phases were washed with brine (1x15 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give a yellow foam. The residue was stirred with HCl, 4.0 M in dioxane (5 ml, 20.00 mmol) at room temperature for 4 hours, and then concentrated in vacuo. The residue was dissolved in a small amount of MeOH and added to 1 M HCl (15 mL). This mixture was extracted with methylene chloride (2 x 15 mL). The aqueous layer was then made basic with saturated aqueous NaHCO 3 solution (at about pH 9) and extracted with methylene chloride (3 * 15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was charged dry on silica gel (0.5 g) and purified by flash chromatography (Analogix, 24 g of S1O2, gradient of DCM to 75% DCM / MeOH / NH4OH 90/10/1 throughout 40 minutes) to give 12 mg of the product. The NMR analysis was not acute, whereby the material was taken up in THF, 4 M HCl in dioxane was added and it was concentrated again in vacuo to give the bis-HCl salt. The material was then purified by reverse phase HPLC HPLC (Gilson, 20 mm x 50 mm C18, gradient of CH3CN in water of 5% to 30% with 0.1% TFA, 8 minutes) to give the desired pure product. The product fractions were concentrated in vacuo, azeotropically distilled twice with acetonitrile, collected in a mixture of DCM and MeOH, and passed through a resin cartridge of MP SratoSpheres SPE PL-HCO3. The filtrate was then concentrated in vacuo to give the free base of 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine (3 mg) in the form of a solid white. LC / MS (ES) m / z = 467 [M + H] +. 1 H NMR (400 MHz, chloroform-d) d 2.93 (t, J = 6.82 Hz, 2 H), 3.08 (t, J = 6.70 Hz, 2 H), 3.36 (t , J = 8.21 Hz, 2 H), 3.84 (s, 2 H), 4.31 (t, J = 8.59 Hz, 2 H), 4.56 (s, 2 H), 6 , 96-7.05 (m, 1 H), 7.05-7.16 (m, 2 H), 7.33 (t, J = 7.96 Hz, 1 H), 7.57 (s, 1 H), 7.81 (s, 1 H), 8.13 (d, J = 8.34 Hz, 1 H).

EXAMPLE 147 3- (1-r (3,5-dimethyl-1 H -pyrazol-1-yl) acetin-2,3-dihydro-1H-indol-5-yl) -1-methyl 1H-pyrazolof3,4-dlpyrimidin-4-amine DIPEA (1. 158 ml, 6.63 mmol) was added dropwise to a stirred mixture of 3- (2,3-dihydro-1 H -indol-5-yl) -1-methyl-1 H-pyrazolo [3,4- d] pyrimidin-4-amine.2HCl (500 mg, 1, 474 mmol) and (3,5-dimethyl-1H-pyrazol-1-yl) acetic acid (239 mg, 1, 474 mmol) in?,? - dimethylformamide (DMF) (10 ml) under a nitrogen atmosphere. The solution was then cooled in an ice bath and T3P (50% by weight in ethyl acetate) (1.053 mL, 1.769 mmol) was slowly added dropwise over 5 minutes. The mixture was left in the ice bath and allowed to warm slowly to room temperature and stirred overnight. The HPLC analysis indicated that some starting material remained, so an additional 0.2 eq (0.175 ml) of dissolution of T3P. After stirring 1 hour, the HPLC analysis showed no change, additional DIPEA (1 eq., 0.26 ml) was added, and stirring was continued for 1 hour, at which time there was no conversion. An additional 24 mg of (3,5-dimethyl-1 H-pyrazol-1-yl) acetic acid was added and the mixture was stirred for 1 hour - without change. The mixture was diluted with water (30 ml) and extracted with chloroform: isopropanol 10: 1 (5 x 25 ml). The combined organic extracts were dried over a2SO4 overnight, then filtered and evaporated. Purification by chromatography on silica gel (Analogix SF25-60g cartridge) eluting with 0-5% methanol-chloroform gave the pure product as an off-white powder. The impure fractions were combined and purified by chromatography on silica gel (Analogix SF15-24g cartridge) eluting with 0-5% methanol-chloroform to give the additional pure product. The combined products were dried under high vacuum to give the 3-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (376 mg) as an off-white powder. LC-MS (ESI) 403.2 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 8.25 (s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7 , 46 (d, J = 8.3 Hz, 1 H), 5.86 (s, 1 H), 5.1 1 (s, 2 H), 4.29 (t, J = 8.5 Hz, 2 H), 3.94 (s, 3 H), 3.30 (d, J = 8.5 Hz, 2 H), 2, 17 (s, 3 H), 2.10 (s, 3 H) (NH2 protons are not observed).

EXAMPLE 148 5- (1 - (r3- (trifluoromethyl) phenynacetyl) -2,3-dihydro-1 H-indol-5-ylH H- pyrrolor-2,3-dlpyrimidin-4-amine A mixture of 5-bromo-7H-pyrrolo [2,3-d] pyrimidin-4-amine (101 mg, 0.474 mmol), 5- (4,4,5,5-tetramethyl-1, 3 , 2-d-oxaborolan-2-yl) -1-. { [3- (t-fluoromethyl) phenyl] -acetyl} -2,3-D-Hydro-1 H-indole (204 mg, 0.474 mmol), Pd2 (dba) 3 (8.68 mg, 0.00948 mmol) and K3P04 (218 mg, 0.948 mmol) in 6 ml of dioxane and 2 ml of water in a microwave tube, degassed and swept with 3x nitrogen, followed by the addition of tri- (t-butyl) phosphonium tetrafluoroborate (5.50 mg, 0.019 mmol). The mixture was degassed and swept with 4x nitrogen. The mixture was heated in an oil bath at 100 ° C. At 4 h, the LCMS analysis showed that there was no starting material. The mixture was cooled to t.a. and EtOAc was added to the mixture. The upper layer of EtOAc was removed from the lower layer with care to avoid disturbance of the rest of Pd. The EtOAc layer was rotary evaporated to dryness to give a pale yellow solid. The solid was purified by flash column (silica cartridge SF 15-24g), eluting with DCM-MeOH in 10% DCM. The fractions with the product were combined and evaporated to dryness. The solid was triturated in MeOH and the residue was filtered and dried to give 5- (1- { [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H-indol-5 -il) -1 H-pyrrolo [2,3-d] pyrimidin-4-amine in the form of an off-white solid. LC / MS [M + 1] + 438. 1 H NMR (400 MHz, DMSO-d 6) d 3.25 (t, J = 8.34 Hz, 2 H), 4.03 (s, 2 H), 4 , 27 (t, J = 8.46 Hz, 2 H), 5.99 (s, 2 H), 7.18 (d, J = 2.27 Hz, 1 H), 7.21 -7.26 (m, 1 H), 7.34 (s, 1 H), 7.58-7.66 (m, 3 H), 7.68 (s, 1 H), 8.09-8.12 (m , 2 H), 1 1, 74 (s, 1 H).

EXAMPLE 149 5- (4-chloro-1-r (6-methyl-2-pyridinyl) acetin-2,3-dihydro-1 H-indol-5-yl) -7-methy 7H-pyrrolof2.3-d1pyrimidin-amine 4-chloro-2, 3-dihydro-1 H-indole To a stirred solution of 4-chloroindole (5 mg, 33.0 mmol) in acetic acid (50 ml) at 12 ° C under nitrogen atmosphere was added sodium cyanoborohydride (6.84 mg, 109 mmol) in portions. The reaction was stirred at 12 ° C for 2 hours. LC S analysis indicated complete conversion, so the reaction mixture was diluted with water (300 ml), cooled in an ice bath and quenched with sodium hydroxide granules in portions, until the mixture was strongly basic The mixture is then extracted with diethyl ether (3 x 200 mL) and the combined organic extracts were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (0-30% EtOAc in hexanes) to provide 4-chloro-2, 3-dihydro-1 H-indole (4.0 g) as a colorless oil. LC-MS (ES) m / z = 154 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.94 (t, J = 8.59 Hz, 2 H), 3.47 (td, J = 8.72, 1, 77 Hz, 2 H), 5.83 (broad s, 1 H), 6.40 (d, J = 7.83 Hz, 1 H), 6.50 (d, J = 8.08 Hz, 1 H), 6.90 (t , J = 7.96 Hz, 1 H). 4-chloro-2,3-dihydro-1 H-indol-1-carboxylate 1,1-dimethyl ethyl ester A solution of 4-chloro-2,3-dihydro-1 H-indole (4.0 g, 26.0 mmol), Boc20 (6.05 mL, 26.0 mmol), DEA (9.10 mL, 52 , 1 mmol), DMAP (0.318 mg, 2.60 mmol) was stirred at room temperature overnight. The LCMS analysis indicated the complete conversion. The reaction mixture was poured into 0.1 N HCl (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the 4-chloro-2,3-dihydro-1 H-indole-1-carboxylate of, -dimethylethyl (6.36 g) as a yellow oily semi-solid. LC-MS (ES) m / z = 198 [M + H-t-Bu] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.51 (s, 9 H), 3.07 (t, J = 8.72 Hz, 2 H), 3.95 (t, J = 8.72 Hz, 2 H), 6.98 (d, J = 8.84 Hz, 1 H), 7, 19 (t, J = 8.08 Hz, 1 H), 7.48 - 7.70 (m, 1 HOUR). 1,3-bromo-4-chloro-2,3-dihydro-1H-indole-1-carboxylate 1,1-dimethylethyl To a solution of 1,1-dimethylethyl 4-chloro-2,3-dihydro-1 H-indole-1-carboxylate (6.36 g, 25.07 mmol) in dichloromethane (DCM) (100 ml) was added a solution of NBS (4.91 g, 27.6 mmol) in dichloromethane (DCM) (200 ml). The reaction was stirred at room temperature for 2 hours. The LCMS analysis indicated a good conversion, whereby the reaction mixture was poured into sodium bicarbonate (saturated solution, 300 ml), and separated. The aqueous layer was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-30% EtOAc in hexanes, 200 g silica gel column) to provide 5-bromo-4-chloro-2,3-dihydro-1 H-indol-1 - 1, 1-dimethylethyl carboxylate (5.5 g) as an off-white solid. LC-MS (ES) m / z = 276, 278 [M + H-t-Bu] +. H-NMR (400 MHz, DMSO-d6) d ppm 1.50 (s, 9 H), 3.01-3.18 (m, 2 H), 3.88-4.03 (m, 2 H), 7.50 - 7.58 (m, 2 H). 4-Chloro-5- (4.4.5.5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-indole-1-carboxylic acid 1,1-dimethylethyl ester A stirred suspension of 1,1-dimethylethyl 5-bromo-4-chloro-2,3-dihydro-1 H-indole-1-carboxylate (5.5 g, 16.54 mmol), bis (pinacolato) diboro ( 5.04 g, 19.84 mmol), adduct of PdCI2 (dppf) -CH2CI2 (0.675 g, 0.827 mmol), potassium acetate (3.25 g, 33.1 mmol) was heated to 100 ° C for one night. The LCMS analysis indicated good conversion and the reaction mixture was allowed to cool, then poured into NaCl (sat. Aq. Solution), H 2 O 1: 1, (200 ml) and ethyl acetate (300 ml), stirred and it was filtered through celite. The resulting mixture was separated and the aqueous layer was extracted with two additional portions of ethyl acetate (2 x 300 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-25% EtOAc in hexanes, 400 g silica gel column) to provide 4-chloro-5- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indole-1-carboxylic acid 1,1-dimethylethyl ester (2.6 g) as a white solid. LC-MS (ES) m / z = 380 [M + H] + and 324 [M + H-t-Buf. 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.29 (s, 12 H), 1.50 (s, 9 H), 3.05 (t, J = 8.84 Hz, 2 H), 3 , 96 (t, J = 8.72 Hz, 2 H), 7.41-7.68 (m, 2 H). 5- (4-amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4-chloro-2,3-dihydro-1 H-indole-1-carboxylate of 1 , 1-dimethylethyl A mixture of 5-bromo-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (510 mg, 2.246 mmol), 4-chloro-5- (4,4,5,5-tetramethyl) -1, 3,2-dioxaborolan-2-yl) -2,3-dihydro-1 H-indol-1-carboxylate 1,1-dimethylethyl ester (853 mg, 2.246 mmol), Pd2 (dba) 3 (103 mg , 0.12 mmol) and potassium phosphate (K3PO4) (954 mg, 4.49 mmol) and (t-Bu) 3PHBF4 (6.52 mg, 0.022 mmol) in 1,4-dioxane (10 mL) and water (3.3 ml) in a sealed tube was heated to 100 ° C on a heated plate with stirring. At this time, the LCMS analysis indicated good conversion, whereby the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 100 ml), and the combined organic extracts were dried over sodium sulfate and concentrated. The residue was dissolved in DCM (approximately 100 ml), concentrated to a minimum volume (approximately 40 ml), then purified by flash chromatography (0-100% EtOAc in hexanes, silica gel column 40 g) to give 5- (4-amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4-chloro-2,3-dihydro-1 H-indole-1-carboxylate of 1.1 -dimethylethyl (0.716 g) as a yellow solid. LC-MS (ES) m / z = 400 [M + H] +. 1 H NMR (400 MHz, DMSO-de) d ppm 1.52 (s, 9 H), 3.14 (t, J = 8.59 Hz, 2 H), 3.74 (s, 3 H), 3 , 96 -4.07 (m, 2 H), 5.73-6.04 (m, 2 H), 7.15-7.26 (m, 2 H), 7.57-7.80 (m , 1 H), 8.13 (s, 1 H). 5 - ^ - c / gold-2.3-d / y7 / dro- H- / ndo / -5- / 7) -7-meffl-7H-jP / > ro / of2,3-dlpyrimidin-4-amine.2HCl A suspension of 5- (4-amino-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4-chloro-2,3-dihydro-1 H-indole-1-carboxylate from 1,1-dimethylethyl (0.716 g, 1.791 mmol) in HCl (4 M, dioxane) (30 mL, 120 mmol) was stirred at room temperature overnight. The LCMS analysis indicated a good conversion. The reaction mixture was concentrated to give 5- (4-chloro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4- amine.2HCl (667 mg, 1.790 mmol, 100% yield) as an off-white solid. LC-MS (ES) m / z = 300 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.05 (t, J = 8.59 Hz, 2 H), 3.56 - 3.63 (m, 2 H), 3.81 - 3.98 (m, 8 H), 6.55 - 6.62 (m, 1 H), 7.01 (d, J = 7.58 Hz, 1 H), 7.49 (s, 1 H), 8.45 (s, 1 H). 5-. { 4-chloro-1-f (6-methyl-2-pyridinyl) acetill-2,3-dft methyl-7H-pyrrolo [2i 3-dlpyrimidin-4-amine To a solution of 5- (4-chloro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amino .2HCl (300 mg, 0.805 mmol), (6-methyl-2-pyridinyl) acetic acid (213 mg, 0.805 mmol), HATU (306 mg, 0.805 mmol), TFA salt, in?,? - dimethylformamide (DMF) ) (50 ml) under a nitrogen atmosphere at 0 ° C was added DEA (0.562 ml, 3.22 mmol). The reaction was stirred overnight at room temperature, then poured into water and stirred for 1 hour. A brown precipitate formed which was collected by filtration and washed with water. The solid was dissolved in approximately 25 ml of chloroform, and purified by flash chromatography (EtOAc in 0-100% chloroform -> MeOH in 0-10% EtOAc, 24 g column) to provide 5-. { 4-Chloro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (144 mg) as a yellow solid. LC-MS (ES) m / z = 433 [M + H] +. 1 H NMR (400 MHz, DMSO-d 6) d ppm 2.45 (s, 3 H), 3.24 (t, J = 8.46 Hz, 2 H), 3.74 (s, 3 H), 4 , 00 (s, 2 H), 4.35 (t, J = 8.46 Hz, 2 H), 5.69 -6.08 (m, 2 H), 7.16 (t, J = 6, 82 Hz, 2 H), 7.20 - 7.25 (m, 2 H), 7.66 (t, J = 7.58 Hz, 1 H), 8.03 (d, J = 8.34 Hz , 1 H), 8.13 (s, 1 H).

EXAMPLE 150 5- (4-chloro-1 - (r6- (trifluoromethyl) -2-pyridinyl-1-acetyl) -2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolor-2,3-d-pyrimidin-4 -amine To a solution of 5- (4-chloro-2,3-dihydro-1 H -indol-5-yl) -7-methyl-7H-pyrrolo [2,3-d] pyridin-4-am Na.2HCl (300 mg, 0.805 mmol), [6- (trifluoromethyl) -2-pyridinyl] acetic acid (90% by weight) (183 mg, 0.805 mmol), HATU (306 mg, 0.805 mmol), in? ,? - dimethylformamide (DMF) (50 ml) under nitrogen at 0 ° C was added DIEA (0.562 ml, 3.22 mmol). The reaction was stirred overnight at room temperature, then poured into water and stirred for 1 hour. A brown precipitate formed which was collected by filtration and washed with water. The solid was dissolved in approximately 25 ml of chloroform and purified by flash chromatography (EtOAc in 0-100% chloroform - >; MeOH in 0-10% EtOAc, 24 g column) to provide 5- (4-chloro-1- {[[6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro] -1H-indol-5-yl.} - 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine (161.5 mg) as an off-white solid LC-MS (ES) m / z = 487 [M + Hf. 1 H NMR (400 MHz, DMSO-d 6) d ppm 3.22-3.30 (m, 2 H), 3.74 (s, 3 H), 4 , 22 (s, 2 H), 4.37 (t, J = 8.34 Hz, 2 H), 5.72 - 6.02 (m, 2 H), 7.18 - 7.25 (m, 2 H), 7.71 (d, J = 7.83 Hz, 1 H), 7.83 (d, J = 7.58 Hz, 1 H), 8.01 (d, J = 8.34 Hz , 1 H), 8.10 (t, J = 7.96 Hz, 1 H), 8.13 (s, 1 H).

EXAMPLE 151 Capsule Composition An oral dosage form is produced to administer the present invention filling a two piece hard gelatin capsule conventional with the ingredients in the proportions shown in the Table I, presented below.

TABLE I INGREDIENTS AMOUNTS 1-methyl-3- [1- (phenylacetyl) -2,3-dihydro-H-indol-5-yl] - 7 mg ÍH-pyrazolo [3,4-d] pyrimidin-4-amine (Compound of EXAMPLE 1 ) Lactose 53 mg Talc 16 mg Magnesium stearate 4 mg EXAMPLE 152 Injectable Parenteral Composition An injectable form is produced to administer the present invention by stirring the 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-7% by weight methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine (compound of 2) in propylene glycol in 10% by volume water.

EXAMPLE 153 Composition of Tablets Sucrose, calcium sulfate dihydrate and an inhibitor of PERK as shown below in Table II, are mixed and granulate in the proportions shown with a gelatin solution to 10% The wet granules are screened, dried, mixed with the starch, talc and stearic acid, sifted and compressed in a compressed.

TABLE II INGREDIENTS AMOUNTS 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -1 H- 12 mg pyrazolo [3,4-d] pyrimidin-4-amine (compound of EXAMPLE 3) calcium sulfate dihydrate 30 mg Sucrose 4 mg 2 mg starch talcum 1 mg Stearic acid 0.5 mg Biological Activity PKR-type endoplasmic reticulum kinase assay (PERK) (HTRF format) PERK enzyme source: the cytoplasmic domain of GST-PERK (536-1 16) was purchased from Invitrogen (www.invitrogen.com) catalog number PV5106.

Substrate source: elF2a: human full-length elF2a-6-His is purified from baculovirus expression in Sf9 insect cells. The elF2 protein is exchanged with buffer by dialysis in PBS, chemically modified by NHS-LC-Biotin and then exchanged with buffer by dialysis in 50 mM TRIS pH 7.2 / 250 mM NaCl / DTT5 mM. The protein is divided into aliquots and stored at -80 ° C.

Inactivation solution: The inactivation solution is prepared at the time and when it is added to the reactions gives final concentrations of antibody against 4 nM F2a-phospho-ser51 (purchased from Millipore, Catalog No. 07-760, www.millipore. com), rabbit-directed IgG labeled with 4 nM Eu-1024 (purchased from Perkin Elmer, catalog No. AD0083), streptavidin 40 nM Surelight APC (purchased from Perkin Elmer, catalog number AD0201) and 15 mM EDTA.

The reactions were carried out in small volume polystyrene plates of 384 black wells (Grenier, No. 784076) in a final volume of 10 μ ?. The reaction volume contains, in final concentrations, 10 mM HEPES, 5 mM MgCl2, 5 μM ATP ?, 1 mM DTT, 2 mM CHAPS, 40 nM biotinylated 6-His-EIF2a and 0.4 nM GST-PERK (536- 1 1 16). The tests were carried out by adding the GST-PERK solution to test plates containing compounds and pre-incubated for 30 minutes at room temperature. The reaction is initiated by the addition of ATP and EIF2a substrate solution. The inactivation solution is added after one hour of incubation at room temperature. The plates are covered for 2 hours at room temperature before determining the signal. The resulting signal is quantified in a Viewlux reader (PerkinElmer). The APC signal is normalized to the europium signal by transforming the data by means of an APC / Eu calculation.

The compounds to be analyzed were dissolved in DMSO to 1.0 mM and serial dilutions of 1 to 3 were made with DMSO over 1 1 dilutions. 0.1 μ? from each concentration to the corresponding well of a test plate. This creates a range of final compound concentrations of 0.000 7 to 10 μ ?.

The data for the concentration-response curves were plotted as% inhibition, calculated with the data reduction formula 100 * (1- (U1-C2) / (C1-C2)) versus the concentration of compound, where U is the unknown value, C1 is the average control value obtained for 1% DMSO and C2 is the average control value obtained for 0.1 M EDTA. The data was fitted with a curve described by: where A is the concentration [M] and minimum, B is the maximum y, D is the factor of the slope, and x is the log- ?? of the compound. The results for each compound were recorded as pCI50 calculated as follows: pCI50 = -Log10 (K).

Abbreviations used APC, Aloficocianina ATP, adenosine triphosphate BSA, bovine serum albumin CHAPS 3 - [(3-Colamidopropyl) -dimethylammonium] -1-propanesulfonate DMSO, dimethylsulfoxide DTT, dithiothreitol EDTA, ethylenediaminetetraacetic acid Eu, Europio HEPES, N- (2-hydroxyethyl) piperazine-N'-2-ethanesulfonic acid HPLC, high performance liquid chromatography / pressure KCI, potassium chloride M, molar mg, milligrams MgC, magnesium chloride my, milliliters mM, millimolar nM, nanomolar pM, picomolar MOPS, 3-morpholinopropanesulfonic acid NaCl, sodium chloride NCBI, National Center for Biotechnology Information PBS, phosphate buffered saline Tris HCI, tris (hydroxymethyl) aminomethane hydrochloride μ? or u, micromolar The activity against PERK in the previous test is tested in the compounds of the invention.

All the compounds of the examples were tested in general according to the above PERK enzyme assay and in at least one experiment had a pIC50 value: > 7.5 against PERK.

The compound of Example 7 was generally tested in accordance with the above PERK enzyme assay and in at least one group of experiments had an average value of pIC5o of PERK of 8.5 against PERK.

The compounds of examples 4, 6, 14, 19, 22, 23, 42, 55, 82, 93, 102, 1 19, 121, 138, and 146 were generally tested in accordance with the PERK enzyme assay above and at least one group of experiments had an average value of pCI50: = 8.6 against PERK.

The compounds of examples 9, 13, 18, 30, 31, 44, 59, 62, 64, 73, 74, 81, 89, 92, 1 1 1, 125, 131, 133, 134, 136, 137 and 143 they were generally tested according to the previous PERK test and at least one group of experiments had an average value of pCI50: = 9.0.

The compounds of examples 28, 29, 33, 34, 37, 45, 46, 53, 71, 90, 91 96, 100, 1 12, 114, 127, 130, 141, 144 and 148 were tested in general agreement with the previous PERK test and at least one group of experiments had a mean value of pCI50: = 9.5.

In the above data, pCI50 is defined as -log (IC50) where the IC50 value is expressed in molar units.

Although the preferred embodiments of the invention are illustrated by the foregoing, it is to be understood that the invention is not limited to the precise instructions described herein and that the right is reserved for all modifications to fall within the scope of the following claims.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. A compound according to Formula I: (i) wherein: R is selected from: bicycloheteroaryl, and bicycloheteroaryl substituted with 1 to 5 substituents independently selected from: halogen, Ci.6 alkyl, Ci-4 alkyloxy, -OH, Ci-4 hydroxyalkyl, -COOH, -CONH2, tetrazole , -CF3, -alkyl (Ci-4) -O-alkyl (Ci-4), -CH2CH2N (H) C (0) OCH2aryl di (alkyl Ci ^ -aminoalkyloxyCi), aminoalkyl (Ci-4), -N02 , -NH 2, -CN, aryl, aryl substituted with 1 to 3 substituents independently selected from: C 1-4 alkyl, di- (C 1-4 alkyl) -amino- (C 1-4 alkyl), fluoro, chloro, bromo , iodo and -CF3, heterocycloalkyl, heterocycloalkyl substituted with 1 to 3 substituents independently selected from: Ci-, di- (alkyl Ci-) alkyl- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF3 , (alkyl Ci-) -heterocycloalkyl,. (C 1-4 -heterocycloalkyl) substituted with 1 to 3 substituents independently selected from: C 1-4 alkyl, di- (C 1-4 alkyl- amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl, di- (Ci-4 alkyl) -amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3; R2 is selected from: aryl, aryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-4 alkyl, alkyloxy d. , -OH, -COOH, -CONH2, -CF3I- (C1-4alkyl) -O- (alkyl d.4), -N02, -NH2 and -CN, heteroaryl, heteroaryl substituted with 1 to 5 substituents independently selected from : fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkyloxy, -OH, -COOH, -CONH 2, -CF 3, - (C 1-4 alkyl) -0- (C 1-4 alkyl), -NO 2, -NH2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C1-alkyl, alkyloxy CM, -OH, -COOH, -CONH2, -CF3, - (alkyl) Ci.4) -O- (Ci-4 alkyl), -NO2, -NH2 and -CN; and R3 is selected from: hydrogen, fluoro, chloro, bromo and iodo; or a salt thereof including a pharmaceutically acceptable salt thereof.

2. The compound of Formula (I), according to claim 1, further characterized in that: R 1 is bicycloheteroaryl substituted with 1 to 3 substituents independently selected from: halogen, d-6 alkyl, Ci-4 alkyloxy, -OH, hydroxyalkyl Ci -4, -COOH, -CONH2, tetrazole, -CF3, -alkyl (C) -0-alkyl (Ci ^), -CH2CH2N (H) C (O) OCH2aryl di (C1-4 alkyl) -aminoalkyl (C1-) 4), (C1-) aminoalkyl, -NO2, -NH2, -CN, aryl, aryl substituted with 1 to 3 substituents independently selected from: C -4 alkyl, di- (C1-4 alkyl) -amino- (C1 alkyl) -4), fluoro, chloro, bromo, iodo and -CF3i heterocycloalkyl, heterocycloalkyl substituted with 1 to 3 substituents independently selected from: Ci-, di- (alkyl Ci) -amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and -CF 3,. (C 1-4 alkyl) -heterocycloalkyl,. (C 1-4 alkyl) -heterocycloalkyl substituted with 1 to 3 substituents independently selected from: C 1-4 alkyl, di- (C 1-4 alkyl) -amino- (C 1-4 alkyl), fluoro, chloro, bromo, iodo and - CF3, heteroaryl, and heteroaryl substituted with 1 to 3 substituents independently selected from: Ci-4 alkyl, di- (Ci-4 alkyl) -amino- (Ci-4 alkyl), fluoro, chloro, bromo, iodo and -CF3; R2 is selected from: aryl, aryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci-alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF3, - (C1-4 alkyl) ) -O- (C 1-4 alkyl), -NO 2, -NH 2 and -CN, heteroaryl, heteroaryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkyl, C 1-4 alkyloxy -, -OH, -COOH, -CF3, - (C 1 -C 4 alkyl alkyl), -NO 2, -NH 2 and -CN, cycloalkyl, and cycloalkyl substituted with 1 to 5 substituents independently selected from: fluoro, chlorine, bromine , iodo, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF 3, - (C 1-4 alkyl) -O- (Ci-) alkyl, -NO 2, -NH 2 and -CN; and R3 is selected from: hydrogen, fluoro and chloro; or a salt thereof including a pharmaceutically acceptable salt thereof.

3. - The compound of Formula (I), according to claim 1, further characterized in that: R1 is selected from: ? 75 R2 is selected from: aryl, aryl substituted with 1 to 3 substituents independently selected from: halogen, Ci-4 alkyl, Ci-4 alkyloxy, -OH, -COOH, -CF3, - (Ci-4 alkyl) -0- ( C1-4 alkyl), -N02, -NH2 and -CN, heteroaryl, heteroaryl substituted with 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, Ci ^ alkyl, Ci-4 alkyloxy, -OH, -COOH , -CF3, - (C1-4 alkyl) -O- (C1-4 alkyl), -NO2, -NH2 and -CN; and R3 is selected from: hydrogen, fluoro and chloro; or a salt thereof including a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, further characterized in that it is selected from: 1-methyl-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -1 H-pyrazolo [ 3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -1 H -pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7H-pyrrolo [2,3- d] pyrimidin-4-amine; 3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (3-pyridinol) thieno [3,2-c] pyridin-4- Amy 1-methyl-4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-indazole-3-amino; 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indo (4-pyridinyl) thieno [3,2-c] pyridin-4-am 1 H-indol-5-yl} -7- (3-pindinyl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-3-yl) thieno [3,2-c] pyridin-4-amine; 4-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H -indazol-3-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (1 H -pyrazol-4-yl) thieno [3,2-c] pyridin-4-amine; 7- (1-methyl-1 H -pyrazol-4-yl) -3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridine -4-amine; 3-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pinmidin-4-amine; 1 -methyl-3-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1 - (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (, 2,3,6-tetrahydro-4-pyridinyl) thieno [3,2-c] pyridine -4-amine; 3- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-d, h-d-1-H-indol-5-yl) t-ene [3,2- c] pyridin-4-amine; 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3- (1- { [3- (methyloxy) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- [1- (2-naphthalenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -7- (4-piperidinyl) thieno [3,2-c] pindin-4-am-7. { 3 - [(dimethylamino) methyl] phenyl} -3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} thieno [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 7-methyl-5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3-. { 2- [5- (4-aminothieno [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indol-1-yl] -2-oxoethyl-benzonitrile; 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-Dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3- (1 - { [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4- d] pyrimidin-4-amine; 7-methyl-5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3 -d] p / rm / d-n-4-amino; 5-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pinmidin-4-amine; 5-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-chlorophthyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amino; 7-methyl-5- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine; 1-methyl-3- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] ] pyrimidin-4-amine; 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3- (1- { [2- (methyloxy) phenyl] -acetyl} -2,3-dihydro-1H-indol-5-yl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 1-methyl-3-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} - H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-4-yl) furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; and 3-. { 1 - [(2,5-difluorophenyl) acetl] -2,3-dihydro-1H-indol-5-yl} -7- (1 H-pyrazol-4-yl) thieno [3,2-c] pindin-4-amine; or a salt thereof including a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, further characterized in that it is selected from: 1-methyl-3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] -1 H-pyrazolo [ 3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluoropheni!) Acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -1 H -pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-di idro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 1-methyl-4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H -indazol-3-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (4-pyridinyl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-pyridinyl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1 H-pyrazol-3-yl) thieno [3,2-c] pyridin-4-amine; 4-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H -indazol-3-amine; 3- [1 - (feni laceti l) -2, 3-dih id ro- 1 H-indol-5-yl] -7- (1 Hp¡razol-4-yl) thieno [3,2-c] pyridine -4-amine; 7- (1-methyl-1 H -pyrazol-4-yl) -3- [1 - (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridine -4-amine; 3-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3-. { 1 - [(3- methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3- [1- (phenylacetyl) -2,3-d, h -dro-1 H -indole-5-yl] -7- (1, 2,3,6-tetrahydro-4) -pyridinyl) thieno [3,2-c] pyridin-4-amine; 3- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 3- (1 - { [3- (methyloxy) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) thieno [3,2-c] pyridin-4-amine; 3- [1- (2-naphthalenylacetyl) -2,3-dihydro-1 H -indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3- [1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7- (4-piperidinyl) thieno [3,2-c] pyridin-4-amine; 7- { 3 - [(dimethylamino) methyl] phenyl} -3- [1- (phenylacetyl) -2,3-dihydro-1 H-indol-5-yl] thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-in ^^ amine; 3-. { 1 - [(3,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} thieno [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(2-methylphenyl) acetyl] -2,3-dihydro-H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} thieno [3,2-c] pyridin-4-amine; 7-methyl-5-. { 1 - [(3- methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} tieno [3, ^ amine; 3-. { 2- [5- (4-aminothieno [3,2-c] pyridin-3-yl) -2,3-dihydro-1 H-indol-1-yl] -2-oxoethyl-benzonitrile; 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(2,3-Dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indodo ^ pyrazolo [3,4-d] pyrimidin-4-amine; 7-methyl-5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H -indol-5-yl) -7H-pyrrolo [2,3- d] pyrimidin-4-amine; 5- { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 amine; 5-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine; 1-methyl-3- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H -pyrazolo [3,4-d] ] pyrimidin-4-amine; 7-methyl-5- (1- { [3- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2,3-d] ] pyrimidin-4-amine; 3-. { 1 - [(2-chlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 1-methyl-3- (1- { [2- (methyloxy) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H -pyrazolo [3,4-d] ] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 1-methyl-3-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-d] pyrimid-4-amino; 5-. { 1 - [(2,5-dimethylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1H-pyrazol-4-yl) furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pinmidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7- (1 H-pyrazol-4-yl) thieno [3,2-c] pyridin-4-amine; 3-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-piperidinyl) -7H-pyrrolo [2,3-c] pinmidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (1-methyl-4-pipendinyl) -7H-pyrrolo [2,3-d] pinmidin-4-amine; 5-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} thieno [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3-chloro-5-fluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(2-Fluoro-5-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 1 -methyl-3-. { 1 - [(1-methyl-1 H -pyrrol-2-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 / - -pyrazolo [3,4-d] pyrimidin-4-amine; 3-. { 1 - [(3-chlorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} furo [3,2-c] pyridin-4-amine; { 1 - [(2,3-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-cf] pinmidin-4-amine; 5-. { 1 - [(2-fluoro-3-methylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-d] pinmidin-4-amine; 5-. { 1 - [(2-fluoro-5-methylphenyl) acetyl] - 2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3 - (^ pyrimidin-4-amine; 3- { 1 - [(2-fluoro-3-methylene] acetyl] -2,3-dih Dro-1 / - / - ndol-5-yl.} -1-metl-1 / - -pyrazolo [3,4-cf] pyridin-4-amine; {. 1 - [(3-Fluoro-2-methylphenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl.} - 1-methyl-1 H-pyrazolo [3,4- d] pyrimidin-4-amine; 5- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.}. -7- (1-methyl) -4-piperidinyl) -7H-pyrrolo [2,3 - (^ pinmidi 5-. { 1 - [(3-chloro-4-fluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3-chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(3-chloro-4-fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-c /] pyrimidin-4-amine; 3-. { 1 - [(3-chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1 H -indole-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5-. { 1 - [(2,3-Dimethylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-c /] pyrimidin-4-amine; 1- (1-methylethyl) -3-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-c pyrimidin-4-amine; 2- (4-amino-3- { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl}. -1H-pyrazolo [3,4-d] ] pyrimidin-1-yl) ethanol; 5-. { 1 - [(3,5-dimethylphenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pinmidin-4-amine; { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (4-pipendinyl) -7H-pyrrolo [2,3-cf] pyrimidin-4-amine; 1 -ethyl- 3-. { 1 - [(3-methylphenyl) acetyl] -2 di ^ amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methylfuro [3,2-c] pyridin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 - (1-methylethyl) -1 / - / - pyrazolo [3,4-cf] pyrimidin-4-amine; 5-. { 1 - [(3,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-c ^ pyrimidin-4-amine; 7-methyl-5-. { 1 - [(2,3,5-trifluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7H-pyrrolo [2,3- (4-pyridine-4-amine; 5- { 1 - [(3,5-dichlorophenyl) acetyl] -2,3-dihydro-1 / - / - indole-5- il.) .7-methyl-7 / - / - pyrrolo [2,3-cf] pinmidin-4-amine; 7- (3-azetidinyl) -5- { 1 - [(3-methylphenyl) acetyl; ] -2,3-dihydro-1 / - / - indol-5-yl.} - 7 H -pyrrolo [2,3-d] pyrimidin-4-amine; 5- { 1 - [(4-fluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl.} - 7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5. 1 - [(4-methylphenyl) acetyl] -2,3-dihydro-1H-indol-5-yl}. -7H-pyrrolo [2,3-cf] pyrimidin-4-amine; - [(3-chloro-2,4-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl.}. -7-methyl-7 / - / - pyrrolo [2,3-d ] pinmidin-4-amine; 5- (1 - { [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7- methyl-7r -pyrrolo [2,3-d] pinmidin-4-amine; 7 - [(methyloxy) methyl] -5- { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1H -indol-5-yl.}. -7H-pyrrolo [2,3-cf] pyrimidin-4-amine; 7-methyl-5- { 1 - [(1-methyl-1 / - / - pyrrol- 2-yl) acetyl] -2,3-dihydro-1H-indol-5-yl}. -7H-pyrrolo [2,3 ^ irimidin-4-amine; 5- { 1 - [(2,5 -diflu orophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7- (1-methylethyl) -7 / - / - pyrrolo [2,3-cf] pinmidin-4-amine; 5-. { 1 - [(5-Chloro-2-fluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-cf] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 ry-indol-5-yl} -7- [2- (4-morpholinyl) ethyl] -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,4-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3,4-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-c] pinmidin-4-amine; [2- (4-amino-3- { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl.} Furo [3,2-c] phenylmethyl pindin-7-yl) ethyl] carbamate; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7- (3-methylbutyl) -7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7- [2- (dimethylam 5-. { 1 - [(6-chloro-2-pyridinyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amino; 3-. { 1 - [(3-chloro-2,4-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -1-methyl-1 / - / - pyrazolo [3,4-c /] pyrimidine-4-amino; 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} furo [3,2-c] pyridin-4-amine; 4-amino-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} furo [3,2-c] pyridine-7-carbonitrile; 5-. { 1 - [(3,5-dimethyl-1H-pyrazol-1-yl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine; 5- [4-fluoro-1- (phenylacetyl) -2,3-dihydro-1 H -indol-5-yl] -7-methyl-7H-pyrrolo [2,3-c /] pyrimidin- 4-amin; 5-. { 4-Fluoro-1 - [(1-methyl-1H-pyrrol-2-yl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-c /] pinmidi 4-amine; 5-. { 1 - [(2,5-D-fluoro-phenyl) -acetyl] -4-fluoro-2,3-d-hydro-1H-indol-5-yl} -7-methyl-7 / - / - pyrrolo [2,3-c /] pnedi n-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} furo [2,3-d] pinmidin-4-amine; 5- (1- { [3- (trifluoromethyl) phenyl] acetl.} -2-d ^ ^ 5- . { 1 - [(3-Chloro-5-fluorophenol) acetyl] -2,3-dihydro-1 / - / - ndol-5-yl} furo [2,3-c] p¡r¡m¡d¡n-4-amine; 5-. { 1 - [(3-methylene] acetyl] -2,3-dihydro-1H-indol-5-yl} furo [2,3-d] pyridr-4-amine; 5- (1- { [3-fluoro-5- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 / - -indol-5-yl) furo [2,3-cf] pinmidin -4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} -7- [2- (4-piperidinyl) ethyl] -7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine; 7-methyl-5-. { 1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7H-pirrolo [2,3 4-amine; 5- (1- { [4-fluoro-3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) -7-methyl-7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7- (3-oxetanyl) -7H-pyrrolo [2,3-c /] pyrimidin-4-am 3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7- [2- (dimethylamino) ethyl] furo [3,2-c] pyridin-4-amine; 7-methyl-5- (1- { [6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1H-indol-5-yl) -7H-pyrrolo [2,3 -c /] pinmidin-4-amine; 7- (3-oxetanyl) -5- (1- {[[3- (tnfluoromethyl) phenyl] acetyl} -2,3-dihydro-1 / - / - indol-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- [2- (4-morpholinyl) ethyl] -5- (1- {[[3- (tnfluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) - 7H-pyrrolo [2,3-c /] pyrimidin-4-amine; 7- (1-methylethyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2 , 3-d] pyrimidin-4-amine; 7- (3-methylbutyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 r -indol-5-yl) -7 / - -pyrrolo [2,3-lpyrimidin-4-amine; 4-. { 1 - [(3-methylphenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1 H-pyrazolo [3,4-c] pi din-3-amine; 7-chloro-3-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 / - / - indol-5-yl} furo [3,2-c] pyridin-4-amine; 7- (3-azetidinyl) -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H-pyrrolo [2 , 3-c /] pinnriidin-4-amine; 7- (1-methyl-3-azetidinyl) -5- (1 - { [3- (tnfluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7H -pyrrolo [2,3-d] pyrimidin-4-amine; 7- [2- (dimethylamino) ethyl] -5- (1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7 / - / - pyrrolo [2,3-d] pihmidin-4-amine; 5- (4-Fluoro-1- {[[3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7 / - / - pyrrolo [2,3-d] pyrimidin-4-amine; 5-. { 4-Fluoro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-c piri amine; 5- (4-fluoro-1- {[[6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H-indolyl] -7-methyl-7H-pyrrolo [ 2,3-d] pyrimidin-4-amine; 5-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-c] pyrimidine amine; 5- (4-fluoro-1- {[4-fluoro-3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H -pyrrolo [2,3-d] pyrimidin-4-amine; 3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 5-. { 4-fluoro-1 - [(4- fluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d3pyrimidtn-4-amine; 4- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1H-indol-5-yl) -1 H -pyrazolo [3,4-c] pyridin-3 amine; 1-methyl-4- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H-pyrazolo [3,4- c] pyridin-3-amine; 7- (3-azetidinyl) -5-. { 1 - [(2,5-difluorophenyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7H-pyrrolo [2,3-d] pyrimidin-4 ^ amine; 7- [2- (4-piperidinyl) ethyl] -5- (1 - { [3- (trifluoromethyl) phenyl] acetyl] -2,3-dihydro-1 H-indol-5-yl) - 7H-pyrrolo [2,3-d] pyrimidin-4-amine; 7- (2-aminoethyl) -3-. { 1 - [(2,5-difluorophenyl) acetyl] -4-fluoro-2,3-dihydro-1 H-indol-5-yl} furo [3,2-c] pyridin-4-amine; 3-. { 1 - [(3,5-dimethyl-1 H -pyrazol-1-yl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -1-methyl-1 H-pyrazolo [3,4-d] pyrimidin-4-amine; 5- (1- { [3- (trifluoromethyl) phenyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -1 H -pyrrolo [2,3-d] pyrimidine- 4-amine; 5-. { 4-Chloro-1 - [(6-methyl-2-pyridinyl) acetyl] -2,3-dihydro-1 H-indol-5-yl} -7-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-amine; and 5- (4-chloro-1- {[[6- (trifluoromethyl) -2-pyridinyl] acetyl} -2,3-dihydro-1 H-indol-5-yl) -7-methyl-7H -pyrrolo [2,3-d] pyrimidin-4-amine; a salt thereof including a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

7. The use of a compound of formula I, as described in claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or reducing the severity of cancer, precancerous syndromes, Alzheimer's disease, stroke, diabetes Type 1, Parkinson's disease, disease of Huntington, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, and age-related macular degeneration, in a mammal

8. The use as claimed in claim 7, wherein the mammal is a human being.

9. The use of a compound of Formula I, as described in claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the activity of PERK in a human.

10. The use of a) a compound of formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof; and b) at least one antineoplastic agent, for the manufacture of a medicament for the treatment of cancer in a mammal.

1. The use as claimed in claim 8, wherein said cancer is selected from: brain (gtiomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, cancer breast, inflammatory breast, Wilm tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovary, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, cell carcinoma acinar, glucagonoma, insulinoma, metastatic melanoma, prostate, sarcoma, osteosarcoma, giant cell tumor, thyroid, lymphoblastic leukemia of T lymphocytes, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, large cell immunoblastic leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T lymphoblastic lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, cancer of the salivary glands, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, cancer mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

12. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises placing the compound of formula (I) ) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient.

13. The use as claimed in claim 8, wherein said precancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammopathy of undetermined significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin moles (pre-melanoma), prosthetic intraepithelial neoplasia (intraductal) (PIN), ductal carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

14. The use of a compound of formula I, as described in claim 1 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or reducing the severity of eye diseases in a human being.

15. The use as claimed in claim 14, wherein the ocular disease is selected from: iris rubeosis; neovascular glaucoma; pterygium; filtering blebs of vascularized glaucoma; papilloma of the conjunctiva; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, anterior, traumatic, or idiopathic uveitis; macular edema; retinal neovascularization due to diabetes; macular degeneration associated with age (AMD); macular degeneration (AMD); ocular ischemia syndrome due to carotid artery disease; ophthalmic or retinal arterial occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale's disease; and VonHippel-Lindau syndrome.